programme, abstracts & floor plan · page 3 abstracts of the 17th biennial congress of the...

UBUNTU: GENETICS

PROGRAMME, ABSTRACTS &FlOOR PlAn

Abstracts of the 17th Biennial Congress of the Southern African Society for Human Genetics

Conference organiser

Petrie Vogel, Tel: +27 12 346 0687Fax: +27 (12) 346 [email protected]

www.savetcon.co.za

layout & designMarina Lubbe Graphic Design

local Organising Committee

Prof Miriam Adhikari University of KwaZulu-NatalProf Colleen Aldous University of KwaZulu-NatalDr Thirona Naicker University of KwaZulu-Natal/ Inkosi Albert Luthuli Central Hospital – Genetics UnitSr Namitha Chabilal Inkosi Albert Luthuli Central Hospital – Genetics UnitSr Marlene Nadesan Inkosi Albert Luthuli Central Hospital – Genetics UnitShelagh Kavonic South African National Blood Services Dr Yugasgnee Naidoo University of KwaZulu-Natal/Edendale Hospital Dr Helen Malherbe University of KwaZulu Natal/Genetics Alliance South AfricaSarah Walters University of KwaZulu-Natal/Ampath LabDr Logie Govender Queen Nandi Regional Hospital

Scientific CommitteeProf Colleen Aldous University of KwaZulu-NatalKaren Fieggen UCTLizette Jansen van Rensburg UPZane Lombard WitsHelen Malherbe University of KwaZulu-NatalThirona Naicker University of KwaZulu-Natal


Welcome to Durban and the 17th biennial South African Society of Human Genetics Conference. KwaZulu-Natal hosted the third and the 10th SASHG conference and much has happened in the last fourteen years. The dynamic teams of genetics nurses, nurse counsellors and our own geneticists have dwindled but the patient demands are still there. The current situation in our province led to our theme ‘Ubuntu Genetics – Why we do what we do’ to remind us that it is the patient and their families who need care and we have to find a way to provide it. Whether we are scientists, nurses, counsellors or doctors, the bottom line is the patient who we should endeavor to provide the best care for.

In reflecting on the years since our last KZN conference, we remember fondly those who went before us. Prof Bill Winship provided the foundation for genetics services across the province. He was a founding member of SAIDA (Southern African Inherited Disorders Association), now GA-SA (Genetics Alliance – South Africa). He was also a founding member of our society, the South African Society for Human Genetics. The SASHG honoured him in 2004 with the endowment of the Bill Winship SASHG Gold Medal for an outstanding trainee in clinical genetics. We will remember him when we open the conference on the first evening.

Sister Lin Wilson was a champion for MGEP and genetics services across the province. She worked closely with Prof Winship and helped knit together efforts across the province with Kwanagen, a group that met to discuss collaborative efforts from across the province a couple of times a year. She was dedicated and energetic and much of her work has led to what our current small team is able to maintain. Sadly Lin is still in Hillcrest Hospital after suffering a pulmonary embolism in 2011.

A conference like the SASHG comes together only with the synergistic efforts of many people. I thank (with honestly the deepest gratitude) the local organizing committee. Petrie and her team from Savetcon were invaluable in showing us the way and helping out with all sorts of things we thought were crises. The scientific committee included scientists, geneticists and counsellors from across the country, but the geography was irrelevant and we managed to review the manuscripts in excellent time. Thank you. In anticipation, I also thank all who have agreed to be session chairs at the conference. It will be a tough task keeping to time this year with the introduction of rapid fire talks.

We have a wonderful series of invited talks to be delivered by eminent speakers from across the globe as well as from our own backyard. We bracket all the speakers with locals, starting off with Prof Miriam Adhikari from UKZN who has dedicated all her life to paediatrics and genetics research, and end with Prof Richard Hift, also from UKZN who as a physician, scientist and academic has become a part geneticist.

Our sponsors ensure that our conference can happen and we are grateful to them. Although we pay a conference fee, we need to look at gathering funds for scholarships for the next conference and we do like to add a little luxury with some extras to make the conference special. The sponsors are all recognized in the program but I would like to especially thank the KZN Department of Health for sponsoring the conference fees for clinicians and nurses from across the province. This sponsorhips will allow extra clinicians from our province to attend and become inspired to join our team who are working together to do the best we can with what we have for those who need us.

We hope you are inspired by the conference and that you have fun too. Please enjoy the opportunity to interact

and share experience, so that we all leave at the end of the conference feeling excited and ready to take on the

challenge of Ubuntu Genetics!

Yours sincerelyColleen AldousChair: SASHG 2017 Organising Committee

Welcome


CardiovascularConnective tissueDisorders in sex development EndocrineFertility & PregnancyGastrointestinal tract & liverHearing impairment Hematological

Hereditary cancerImmunologicalIntellectual Disability LungMetabolicMitochondrial Multi-Organ

Neurological Neuromuscular PharmacogeneticsRenalSkeletalSkinVision impairment

DISORDERS

Solving the genetic puzzle of your patients“High quality diagnostics of genetic disorders”

Exome sequencing diagnosticsMultiple gene diagnostics

Single gene diagnosticsMutation diagnostics

Array diagnosticsChromosome diagnostics

Exome sequencing diagnosticsMultiple gene diagnostics

Single gene diagnosticsMutation diagnostics

Array diagnosticsChromosome diagnostics

SERVICES

www.genomediagnosticsnijmegen.nl [email protected] +31 24 36 13 799


Floor plan

1 Abela Africa Medical

2 Ampath Trust

3 Biocon Biotech

4 CGat GmbH

5 CPGR

6 Diagnostech

7 Genesis Genetics

10 Inqaba Biotechnical Industries (Pty) Ltd

13 Invitae (International Company)

8 & 9 Perkinelmer South Africa (Pty) Ltd

14 & 15 Sanofi Genzyme

12 & 11 Shire Pharmaceuticals South Africa(Pty) Ltd

16 The Scientific Group

17 Thermo Fisher Scientific

18 Whitehead Scientific (Pty) Ltd

Foyer SASHG

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10

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13

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9 8 7 6


SponSorSPlatinum

Gold

Silver

Bronze

Exhibitor

WhiteSciWhitehead Scientific (Pty) Ltd

Products. Expertise. Support.

Company

A


programmeSunday 13 August 2017Start End Speaker Title of talk15:00 17:00 Registration in the Congress Foyer

Opening: Chair: Colleen Aldous17:00 17:30 Learners from West Park School

17:30 17:45 Zane Lombard Opening and welcome by SASHG chair

17:45 18:00 Neil McKerrow Opening address

18:00 18:15 Thirona Naicker Address from organising committee

18:15 18:45 Prof Miriam Adhikari Opening address

18:45 Welcome and ice breaker dinner - Great Ilanga - Elangeni Hotel

Monday 14 August 2017Session Title: Genetic Counselling Chair: Tina Wessels 7:00 8:30 Registration in the Congress Foyer

8:30 9:00 Anna Middleton Socialising the Genome

9:00 9:10 Jennifer Kromberg Children with oculocutaneous albinism: challenges and management

9:10 9:20 Amber Ross The complexities of genetic counselling for nonsyndromic hearing impairment in the South African context

9:20 9:30 Nakita Laing Genetic counselling in Cardio-genetic research: A case report of CDH2

9:30 9:37 Clair Engelbrecht Perceptions of Health Related Quality of Life among Adults living with Sickle Cell Disease in Cape Town, South Africa

9:37 9:44 Tabitha Haw Black South African women’s perspectives on the impact of having a baby with a genetic disorder on their spousal relationship

9:44 9:51 Chantel van Wyk Microteaching technique can be an efficient technique to train the genetics educator

Tea

Session Title: Prenatal Chair: logie Govender10:35 11:05 Ingrid Winship Precision medicine: reducing the burden of disease by prevention through

genetics and genomics.

11:05 11:15 Jaysen Knezovich Indications for testing and chromosome aneuploidy pick-up rates in patients referred for non-invasive prenatal testing (NIPT) in South Africa

11:15 11:25 Jaysen Knezovich Chromosomal aneuploidy rates and distribution in embryos generated in the South African fertility setting

11:25 11:35 Katryn Fourie Assessment of genetic counselling services and genetic testing uptake in a prenatal setting

11:35 11:45 Malebo Malope Exploring the decision-making process of women offered termination of pregnancy for a serious congenital abnormality

11:45 11:52 Bianca Carzis An Evaluation of Preimplantation Genetic Diagnosis Outcomes in Johannesburg, South Africa

lunch Poster viewing + Thermofischer TalkSession Title: Clinical Genetics Chair: Engela Honey13:00 13:30 Maximilian Meunke Genetics and Genomics of Holoprosencephaly

13:30 13:40 Helen Malherbe Modelled epidemiological data for congenital disorders in South Africa

13:40 13:50 Amanda Krause Huntington disease in South Africa - where are we?

13:50 14:00 Ambroise Wonkam Genetics of Non Syndromic Hearing Loss in Africa

14:00 14:10 Candice Feben Fanconi anaemia - past, present and future in a South African context

14:10 14:20 Manogari Chetty Dental and Craniofacial Manifestations of thin bone disorders in SA

14:20 14:27 Louisa Bhengu Rare Neuro-Metabolic Conditions can be diagnosed early

Tea


Session Title: Molecular Genetics: Sequencing Chair: Zane lombard15:00 15:30 Swaroop Aradhya Choosing the right test for the right patient: from panels to exome

15:30 15:40 Noluthando Manyisa A bioinformatics analysis of the genetics of hearing impairment in a Cameroonian population using whole exome sequencing.

15:40 15:50 Tinashe Chikowore Exploration of the genetic variants associated with type 2 diabetes using novel whole-genome sequences in individuals of Setswana descent in South Africa

15:50 16:00 Craig Kinnear Exome sequencing identifies a novel TTC37 mutation in the first reported case of Trichohepatoenteric syndrome (THE-S) in South Africa.

16:00 16:10 Brigitte Glanzmann Exome sequencing of the first reported South African X-linked primary immunodeficiency case identifies a hemizygous mutation in MSN

16:30 18:00 SASHG Biannual Meeting18:30 Indian evening Dinner - Maharani Hotel, Pannini Restaurant

Tuesday 15 August 2017Session Title: Parkinsons Chair: Karen Fieggen7:00 8:00 Registration in the Congress Foyer

8:00 8:30 Jim Wilson Sex-specific inbreeding depression in humans

8:30 8:40 Oluwole Ooluwafemi Genetic screening in black South African Parkinson’s disease patients for pathogenic mutations using a targeted resequencing approach

8:40 8:50 Annika Neethling A novel interaction identified between LRRK2 and the TOM protein complex which provides possible clues to the aetiology of Parkinson's disease

8:50 9:00 Kamogelo Lebeko Whole exome sequencing for mutation discovery in South African pedigrees with Parkinson's disease

9:00 9:10 Boiketlo Bibi The use of whole exome sequencing to investigate the aetiology of familial Parkinson's disease in a South African Afrikaner family.

9:10 9:17 Hannah-Ruth Engelbrecht

The Pathway to Elucidating Bipolar Disorder Genetics

9:17 9:50 Glenda Sobey Ehlers Danlos Syndrome - A National Diagnostic Service

TeaSession Title: Testing Chair: Raj Ramesar10:30 10:40 Lindsay Lambie Chromosomal Microarray as a First Line Diagnostic Test in Patients with

Congenital Abnormalities/Developmental Delay in South Africa

10:40 10:50 Alina Esterhuizen Delineation of the Genetic Causes of Epileptic Encephalopathy in South African Paediatric Patients

10:50 11:00 Jacqueline Frost The Wnt pathway in Systemic sclerosis

11:00 11:10 Surita Meldau High incidence, clinical presentation and proposed disease mechanism of mitochondrial neurohepatopathy in 22 Black South African infants homozygous for a novel pathogenic variant in the MPV17 gene.

11:10 11:20 Lisa Roberts Genetic analysis of inherited retinal diseases in indigenous Southern African populations

Session Title: South African Human Genome Programme Chair: Michael Pepper11:20 11:35 Michele Ramsay Update on the SAHGP

11:35 11:50 Raj Ramesar Education and Outreach

11:50 12:05 Glaudina Loots Perspectives from the DST

12:05 12:20 Soraya Bardien-Kruger Where to next

lunch Rare Diseases-SA and Genetics Aliance-SA Talks + Poster Viewing

Session Title: Techniques Chair: Shelagh Kavonic13:10 13:20 Nikola Schlechter Identification of novel candidate genes for susceptibility to tuberculosis by

identifying disease-causing mutations in individuals with PIDs

13:30 13:40 Ananyo Choudhury Designing the H3Africa genotyping array

13:40 13:50 Thandiswa Ngcungcu Keratolytic winter erythema: From chromosomal localisation to causal mutation in 20 years

13:50 14:00 Cheryl Stewart Transforming the Way Cystic Fibrosis Is Diagnosed


14:10 14:20 Melissa Nel Gene expression profiling of myocyte cultures identifies perturbed gene networks in ophthalmoplegic Myasthenia Gravis

14:20 14:30 Liesl Hendry MetaboBTT: a queryable cardiometabolic database and web interface for the Birth to Twenty and Metabochip data

TeaSession Title: Diagnostics Chair: Amanda Krause15:00 15:10 Tshepiso Masekoameng Sickle Cell Trait (SCT) and Alpha-thalassemia and targeted genomic variants in

Chronic Kidney Disease (CKD).

15:10 15:17 Heidre Bezuidenhout Review of Chromosomal microarray testing in the postnatal setting at Tygerberg Hospital

15:17 15:24 Sarah Walters Experience of the first abnormal array CGH cases in a diagnostic setting in SA

15:24 15:31 Elana Vorster Diagnostic testing for MECP2-related disorders. A 12 year review at the Division of Human Genetics, NHLS, Johannesburg.

15:31 15:38 Keleabetswe Mpye Genetic Variations in SDHD and TMEM127 in Familial Paraganglioma-Pheochromocytoma

15:38 15:45 Quintin Goodyear Determining whether single MLPA probe deletions are true deletions or false positive results due to mismatch probe binding in patients with developmental delay using Sanger sequencing

16:00 17:30 Dysmorphology Clinical Meeting/Speakers from Invitae, Discovery, Agilent18:00 Gala Dinner at Ushaka Aquarium

Wednesday 16 August 2017Start End Speaker Title of talkSession Title: Cancer Genetics Chair: Michele Ramsay7:00 8:30 Registration in the Congress Foyer

8:30 9:00 Chris Mathew Genome instability in human congenital disorders

9:00 9:10 Raj Ramesar A Child with a Homozygous Mismatch Repair Gene Mutation in a Lynch Syndrome Family Reveals Novel Insights into Carcinogenesis

9:10 9:20 Reabetswe Pitere Investigating cancer susceptibility genes in black South African breast cancer individuals

9:20 9:30 Mpoi Makhetha Screening of high-risk BRCA1/2 mutation negative women for mutations in PALB2

9:30 9:40 Mardelle Schoeman BRCA counselling and testing at Tygerberg Hospital: 2008-2016

TeaSession Title: Anthropology Chair: Himla Soodyall10:10 10:40 Carina Schlebush The Genetic History of Africa

10:40 10:50 Dhriti Sengupta An Ancestry Informative Marker panel designed for analysing stratification in African populations

10:50 11:00 Francisco Ceballos Runs of Homozygosity in Africa: Insights into the more complex picture of African population genetics

11:00 11:10 Himla Soodyall Appearance and Reality: Unpacking Racial Profiling

Session Title: Teaching/Pharmacogenetics Chair: Colleen Aldous11:25 11:35 Kagisho Montjane Pharmacogenetics of tenofovir

11:35 11:45 Kudakwashe Mhandire KIR gene content variation influences immune activation in antiretroviral therapy-naïve adult Zimbabweans

11:45 11:55 Helen Malherbe The consequence of terminology related to congenital disorders

11:55 12:25 Richard Hift Bench to Bedside Genetics

12:30 12:45 LOC Chair Vote of Thanks and Prize Giving

12:45 13:00 SASHG Chair Closing remarks

13:00 lunch


InVITED SPEAKERS................ 12

MIRIAM ADHIKARI ...........................12

SWAROOP ARADHYA ....................13Choosing the right test for the right patient: from panels to exome .................................................................13

DIDIER GOIDIn .................................14

RICHARD HIFT .................................15Bench to Bedside Genetics ...............................................15

PROFESSOR CHRIS MATHEW .......16Genome instability in human congenital disorders ........16

AnnA MIDDlETOn ..........................17Socialising the Genome .....................................................17

MAxIMIlIAn MUEnKE .....................18Genetics and Genomics of Holoprosencephaly ..............18

CARInA SCHlEBUSCH ...................19Genetic history of Africa ....................................................19

DR GlEnDA SOBEY ........................20Ehlers Danlos Syndrome - A national Diagnostic Service .................................................................................20

JIM WIlSOn .....................................21Sex-specific inbreeding depression in humans ..............21

InGRID WInSHIP ..............................22Precision medicine: reducing the burden of disease by prevention through genetics and genomics ...............22

ORAl ABSTRACTS ................. 23

MOnDAY 14 AUGUST 2017 .............23Socialising the Genome .....................................................23

Children with oculocutaneous albinism: challenges and management ................................................................24

The complexities of genetic counselling for nonsyndromic hearing impairment in the South African context ...................................................................25

Genetic counselling in Cardio-genetic research: A case report of CDH2 ...........................................................26

Perceptions of Health Related Quality of life among Adults living with Sickle Cell Disease in Cape Town, South Africa ...................................................27

Black South African women’s perspectives on the impact of having a baby with a genetic disorder on their spousal relationship ..................................................28

Microteaching can be an efficient technique to train the genetics educator ........................................................29

Precision medicine: reducing the burden of disease by prevention through genetics and genomics. ..............30

Indications for testing and chromosome aneuploidy pick-up rates in patients referred for non-invasive prenatal testing (nIPT) in South Africa ......31

Chromosomal aneuploidy rates and distribution in embryos generated in the South African fertility setting 32

Assessment of genetic counselling services and genetic testing uptake in a prenatal setting.....................33

Exploring the decision-making process of women offered termination of pregnancy for a serious congenital abnormality. .....................................................34

An Evaluation of Preimplantation Genetic Diagnosis Outcomes in Johannesburg, South Africa ....35

Genetics and Genomics of Holoprosencephaly ..............36

Modelled epidemiological data for congenital disorders in South Africa ...................................................37

Huntington disease in South Africa - where are we? ......38

Genetics of non Syndromic Hearing loss in Africa .......39

Fanconi anaemia – past, present and future in a South African context ........................................................40

Dental and Craniofacial Manifestations of OI III in SA ....41

Rare neuro-metabolic conditions can now be diagnosed and treated early with increasing availability of genetic testing for founder mutations in Black South African families. 3 cases reports discussed. ...........................................................................42

Choosing the right test for the right patient: from panels to exome .................................................................43

Whole exome sequencing identifies causative mutations in autosomal recessive nonsyndromic hearing loss patients from Sub-Saharan Africa ..............44

A bioinformatics analysis of the genetics of hearing impairment in a Cameroonian population using whole exome sequencing. .................................................45

Exploration of the genetic variants associated with type 2 diabetes using novel whole-genome sequences in individuals of Setswana descent in South Africa ........................................................................46

contentS

Abstracts of the 17th Biennial Congress of the Southern African Society for Human GeneticsExome sequencing identifies a novel TTC37 mutation in the first reported case of Trichohepatoenteric syndrome (THE-S) in South Africa. 47

Exome sequencing identifies a novel TTC37 mutation in the first reported case of Trichohepatoenteric syndrome (THE-S) in South Africa. 48

Exome sequencing of the first reported South African X-linked primary immunodeficiency case identifies a hemizygous mutation in MSN ........................49

TUESDAY 15 AUGUST 2017 ............50Sex-specific inbreeding depression in humans ..............50

Genetic screening in black South African Parkinson’s disease patients for pathogenic mutations using a targeted resequencing approach ......51

A novel interaction identified between LRRK2 and the TOM protein complex which provides possible clues to the aetiology of Parkinson’s disease .................52

Whole exome sequencing for mutation discovery in South African pedigrees with Parkinson's disease ........53

The use of whole exome sequencing to investigate the aetiology of familial Parkinson’s disease in a South African Afrikaner family ..........................................54

The Pathway to Elucidating Bipolar Disorder Genetics .55

Ehlers Danlos Syndrome - A national Diagnostic Service .................................................................................56

Chromosomal Microarray as a First line Diagnostic Test in Patients with Congenital Abnormalities/Developmental Delay in South Africa ...............................57

Delineation of the genetic causes of epileptic encephalopathy in South African paediatric patients. ....58

The Wnt pathway in Systemic sclerosis ..........................59

High incidence, clinical presentation and proposed disease mechanism of mitochondrial neurohepatopathy in 22 Black South African infants homozygous for a novel pathogenic variant in the MPV17 gene. .............................................................60

Genetic analysis of inherited retinal diseases in indigenous Southern African populations .......................61

Identification of novel candidate genes for susceptibility to tuberculosis by identifying disease-causing mutations in individuals with PIDs ......62

Designing the H3Africa genotyping array ........................63

Keratolytic winter erythema: From chromosomal localisation to causal mutation in 20 years .....................64

Transforming the Way Cystic Fibrosis Is Diagnosed ......65

Gene expression profiling of myocyte cultures identifies perturbed gene networks in ophthalmoplegic Myasthenia Gravis ................................66

MetaboBTT: a queryable cardiometabolic database and web interface for the Birth to Twenty and Metabochip data .................................................................67

Sickle Cell Trait (SCT) and Alpha-thalassemia and targeted genomic variants in Chronic Kidney Disease (CKD). ....................................................................68

Review of Chromosomal microarray testing in the postnatal setting at Tygerberg Hospital ...........................69

Experience of the first abnormal array CGH cases in a diagnostic setting in SA .............................................70

Diagnostic testing for MECP2-related disorders. A 12 year review at the Division of Human Genetics, nHlS, Johannesburg. ........................................................71

Genetic Variations in SDHD and TMEM127 in Familial Paraganglioma-Pheochromocytoma..................72

Determining whether single MlPA probe deletions are true deletions or false positive results due to mismatch probe binding in patients with developmental delay using Sanger sequencing .............73

WEDnESDAY 16 AUGUST 2017 .....74Genome instability in human congenital disorders ........74

A Child with a Homozygous Mismatch Repair Gene Mutation in a lynch Syndrome Family Reveals novel Insights into Carcinogenesis..................................75

Investigating cancer susceptibility genes in black South African breast cancer individuals ..........................76

Screening of high-risk BRCA1/2 mutation negative women for mutations in PALB2 ........................................77

BRCA counselling and testing at Tygerberg Hospital: 2008-2016 ............................................................78

The Genetic History of Africa ............................................79

An Ancestry Informative Marker panel designed for analysing stratification in African populations ...............80

Runs of Homozygosity in Africa: Insights into the more complex picture of African population genetics ...81

APPEARAnCE AnD REAlITY: UnPACKInG RACIAl PROFIlInG ..........................................................................82

Pharmacogenetics of Tenofovir ........................................83

Killer Cell Immunoglobulin-like Receptor (KIR) gene content variation influences immune activation in antiretroviral therapy naïve adult Zimbabweans .............84

The consequence of terminology related to congenital disorders ..........................................................85

Bench to Bedside Genetics ...............................................86

POSTERS ................................. 87


InvIted SpeakerSMiriam AdhikariProfessor Adhikari obtained her MBChB at the University of Cape Town, the Fellowship in Paediatrics from the Colleges of Medicine of South Africa and the PhD from the University of Natal.

Professor Miriam Adhikari is an Emeritus Professor of Paediatrics. She was head of the Department of Paediatrics at UKZN for ten years from 2001 to 2010. During this period the existing functions of the Department, service teaching and research, created by the previous head were expanded.

The service platform was increased, the teaching platform was expanded along with the development of the appropriate curriculum, and, research was a critical component that was emphasised in the Department. Further, outreach activities were developed within the service and teaching platforms.

She has published widely in peer reviewed journals, written chapters in books. She is a reviewer for local and international journals in the fields of neonatology and paediatric nephrology. Currently Professor Adhikari is the scientific advisor for the Postgraduate office and is involved in paediatric aspects of the MBChB programme.


Swaroop Aradhya Ph.D., FACMG

Dr. Aradhya is a board-certified molecular geneticist and cytogeneticist who has helped shape professional practices and technology applications in clinical genetic testing over the past 15 years. He joined Invitae to help bring genetics into mainstream medicine by innovating laboratory technologies, fostering advances in evidence-based clinical standards, and building mechanisms to empower individuals globally to access their genetic information. Before Invitae, Swaroop was VP and senior laboratory director for Neurogenetics and Clinical Microarrays at GeneDx. He completed medical genetics training in 2007 at Stanford University and received his Ph.D. in molecular and human genetics in 2001 at Baylor College of Medicine. Over the course of his career, he has participated in the international Human Genome Project to sequence the X chromosome and helped characterize several genetic disorders. He is currently a ClinGen investigator, serves on the Board of Directors of the American Board of Medical Genetics and Genomics, and is an adjunct clinical associate professor at Stanford University School of Medicine.

CHOOSInG THE RIGHT TEST FOR THE RIGHT PATIEnT: FROM PAnElS TO ExOME

Summary:Clinical whole exome sequencing WES) is increasingly being used for diagnosing disorders with broad clinical and genetic heterogeneity. In addition, it is empowering discovery and characterization of novel syndromic pediatric disorders. However, for a number of childhood disorders multi-gene panel sequencing is appropriate and adequate as a first test, and deciding between panels versus WES is a common question in the clinic. On a technical level, clinical-grade WES requires high-quality sequencing and sufficient coverage of all targeted genes. Achieving this quality can be a challenge for any one next-generation sequencing (NGS) workflow and customization is often necessary. In addition, not all NGS methods can produce data on the full spectrum of genetic variants responsible for Mendelian disorders. This seminar will describe the clinical utility of WES, its technical details and limitations, and application in clinical vs research settings.


Didier GoidinDidier Goidin is a clinical genomics field application scientist at Agilent Technologies. He received his Ph.D. in molecular and cellular pharmacology from Pierre and Marie Curie University in Paris in 2000, analyzing rat pituitary tumors with array technology. He joined Agilent technologies in 2001 initially focusing on Bioanalyzer and Gene Expression array projects. With the expansion of array comparative genomic hybridization (aCGH) in Europe, he gained expertise in cytogenetics, including prenatal, postnatal and cancer genetics applications.

Since 2008, he has been working on next generation sequencing (NGS) target enrichment projects, helping in the design of custom libraries in various domains. Over time he has become specialized in creating customized designs for both clinical microarray and NGS applications (Malan et al., Cyto Gen Res 2016, Alesi et al., Genet Syndr Gene Ther 2016). Recently, he has participated in a project using Agilent’s OneSeq assay within a diagnostic environment, ultimately resulting in the diagnostic application of a capture based NGS test for the concurrent detection of variants in sequence, copy number and loss of heterozygosity (Vetro et al, Clin Genet 2017).


Richard HiftHe qualified from the University of Cape Town with the MB ChB degree in 1981 and performed his internship at Groote Schuur Hospital. He specialised in Internal Medicine at the University of Cape Town and Groote Schuur Hospital, becoming a Fellow of the College of Physicians of South Africa in 1987 and a Fellow of the Royal College of Physicians of UK in 2009. He was awarded the Masters in Medicine (Medicine) degree in 1992 with a dissertation entitled Activated Charcoal in the Treatment of Porphyria, and the PhD (Medicine) degree in 2000 with a dissertation entitled Variegate porphyria: molecular aspects and their clinical and biochemical consequences.

His research interests cover all aspects of porphyria, including its epidemiology, natural history, diagnosis and management of variegate porphyria as well as its the pathogenesis,

molecular biology and enzymology, and iron-loading disorders in relation to hereditary haemochromatosis and porphyria cutanea tarda in non-Caucasoid populations. He has 79 peer-reviewed articles, published or in press in a variety of Biochemical, Genetics, Medicine, Hepatology and medical Education journals, including Nature Genetics, and more than 20 chapters in books as well as numerous publications in other media.

BEnCH TO BEDSIDE GEnETICS

A close collaboration between laboratory and clinician is of critical value in many fields of medicine, and in genetics more than most. Cooperation between the laboratory-based scientist and the clinician has proven critical to the development of the diagnostic and therapeutic approaches on which successful management of patients is based. Such cooperation is particularly fruitful when the clinician and the non-clinical scientist have an excellent and intuitive understanding of each other’s fields.

In this talk this is illustrated by three examples based on inherited disorders of haem synthesis, the porphyrias. Protoporphyria long presented a puzzle, since the pattern of inheritance conformed with neither a typical autosomal recessive nor dominant pattern; indeed it was often termed “pseudo-dominant”. This was subsequently explained as the result of co-inheritance of a recessive gene in trans-to a common polymorphism associated with reduced gene expression. A new twist has been the more recent identification of a clinical disorder almost identical in clinical presentation to protoporphyria, but where the mutation besides on a different gene on the X chromosome with a completely different function. Furthermore this gene already has a well-characterised association with a very different group of genetic disorders, X-linked sideroblastic anaemia. The deviation from the normal clinical consequences of inheritance of these X-linked mutations and their convergence with protoporphyria is dependent on a gain of function.

The second is with reference to the so-called Royal malady: the suggestion that the British Royal family carry a gene for variegate porphyria (the commonest monogenetic disorder in South Africa), and that this might have had an important role in history, being responsible for the insanity and erratic rule of King George III, during whose reign Britain lost the American colonies. Yet a disciplined scientific approach based on an understanding of the limitations of diagnosis based on clinical considerations alone and appropriate use of a population genetics approach, combined with Bayesian analysis, should lead to an emphatic rejection of this hypothesis.

The third is in terms of therapy. The porphyrias are a heterogeneous group of disorders. Advances in understanding of these disorders at the molecular level has permitted the development of a number of therapeutic approaches, ranging from the coarse (whole organ transplantation) to gene replacement, gene modification and siRNA-based therapy.


Professor Chris MathewChristopher Mathew is a Distinguished Professor in Human Genetics in the Faculty of Health Sciences at Witwatersrand University, based at the Sydney Brenner Institute for Molecular Bioscience. He also holds a joint appointment as Professor of Molecular Genetics in the Division of Genetics and Molecular Medicine in the Faculty of Life Sciences and Medicine at Kings College London. His main research interest is the investigation of genetic factors which contribute to the development of African cancers, and of genomic changes which are driving tumour development. He is an A rated NRF scientist, and his contribution to an increased understanding of the genetics of human disease was recognised by his election as a Fellow of the Academy of Medical Sciences UK in 2001.

GEnOME InSTABIlITY In HUMAn COnGEnITAl DISORDERS

The connection between defects in DNA repair, which lead to genome instability, and human congenital disorders, has been established for many years. DNA repair defects often also cause predisposition to childhood or adult onset cancers. An exemplar of this connection is the chromosome breakage syndrome, Fanconi anaemia (FA), which is a mainly autosomal recessive disorder associated with microcephaly, radial ray abnormalities and structural defects of internal organs, but also with a very high risk of leukaemia and squamous cell cancers of the head and neck. In adults, heterozygosity for mutations in some of the many FA genes, such as BRCA2, confer an increased risk of breast and ovarian cancer. Recently, in a collaboration with the groups of Grant Stewart, Andrew Jackson and Fowzan Alkuraya, we showed that mutations in a hitherto orphan gene of unknown significance called DONSON, cause microcephalic dwarfism (Reynolds JJ et al, Nature Genetics 49: 537-549). Functional studies showed that DONSON encodes a protein which is critically important for mammalian DNA replication and genome stability. This work exemplifies the principle that the study of rare human genetic disorders can lead to important insights into basic pathways in mammalian biology.


Anna MiddletonDr Anna Middleton is Head of Society and Ethics Research at the Wellcome Genome Campus in Cambridge, UK. She is a genetic counsellor and also a psychologist and leads a team of academics who collectively explore the Ethical, Legal and Social issues raised by genomics. She is continually asking: ‘how is genomics impacting on people?’ and aims to find evidence-based ways to make genomics resonate for patients and their families. She is a previous vice-chair of the Genetic Counsellor Registration Board (UK and ROI) and a current vice-chair of the Association of Genetic Nurses and Counsellors. Together with genetic counselling colleagues she has co-written the core curriculum for training genetic counsellors in the UK and leads the Masters level communication modules for the MSt Genomic Medicine course at the University of Cambridge. Follow Anna on Twitter at @genomethics.

SOCIAlISInG THE GEnOME

Sequencing technologies are transforming medicine in the UK. However recent research has discovered a major stumbling block: only a minority of the British public understands and can relate to even the simplest of terms used in genetics. Because this problem could threaten to blunt the impact of genetics-based medicine – the Socialising the Genome project was designed. Anna will discuss her research and endeavours to turn genomics from (what is for many) an anti-social concept (‘I won’t understand it’, ‘I didn’t do science at school’) to a more social concept. She will explore her work with advertising experts, to create a series of evidence-based animations to explore different ways to help the general public start conversations about genetics (e.g. trying out socially acceptable words like ‘glitch’ in replacement for ‘variant’). She will also discuss and share the films she has created to bring the public to her research about DNA and Big Data. Being able to contribute to current discussions about genomics requires researchers to make the dialogue accessible, even using the simplest of genomics terminology has the capacity to alienate the very people they want to engage. ‘Socialsing the Genome’ is a frame of mind that permeates Anna’s approach to research, it is grounded in her clinical experience of working directly with families in the NHS as a genetic counsellor.

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Maximilian MuenkeSenior Investigator and Chief, Medical Genetics Branch; Director, nIH Medical Genetics and Genomic Medicine Residency and Fellowship Programs

He serves as the Chief of the Medical Genetics Branch of the Division of Intramural Research at the National Human Genome Research Institute, National Institutes of Health (NIH) and the Director of the NIH Medical Genetics and Genomic Medicine Residency and Fellowship programs.

The focus of his laboratory’s research has been on the delineation and identification of the underlying causes of craniofacial anomalies in humans: holoprosencephaly and other craniofacial anomalies, craniosynostosis syndromes including the most common one, Muenke syndrome, and congenital cardiac anomalies.

With the initial successes of gene identification for various monogenic craniofacial disorders and advances in technology he has studied more genetically complex disorders including:1) the most common malformation at birth, congenital cardiac disorders, 2) the most common liver disease in children and adults, non-alcoholic fatty liver disease (NAFLD), and 3) the most common behavioral disorder of childhood, attention deficit hyperactivity disorder (ADHD).

GEnETICS AnD GEnOMICS OF HOlOPROSEnCEPHAlY

Maximilian Muenke1, Paul S. Kruszka1, Benjamin D. Solomon1,2, Donald W. Hadley1, Rachel A. Hart1, Yonit Addissie1, Yu Abe1, Ariel F. Martinez1, Sung-Kook Hong1,

Ping Hu1, Erich Roessler1 and Clinicians around the World1Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA;

2GeneDx, Gaithersburg, MD, USA (M.M. contact: [email protected])

Holoprosencephaly (HPE) is the most common anomaly of the developing forebrain with an incidence of 1 in 250 embryos and 1 in 10,000 live-born infants. HPE has a wide continuum of severity and most individuals show varying degrees of developmental and intellectual disabilities (for a detailed review see Muenke et al. 2010). Both, genetic mutations and environmental exposures have been found to be responsible for HPE. We and others have discovered over a dozen genes associated with HPE and illuminated a number of key molecular pathways involved in human early embryonic development. However, these genes together only account for 20 % of documented HPE cases which emphasizes the need for further investigation into the etiology of HPE.

Approximately 2000 individuals with HPE and their parents (HPE) have been enrolled in our study: 396 individuals representing 157 unrelated kindreds had deleterious mutations (defined as non-sense, deletions, slice site, or missense with deleterious zebrafish assay) in SHH, 157 individuals from 119 unrelated kindreds had mutations in ZIC2, 138 individuals representing 77 unrelated kindreds had mutations in SIX3, and 34 individuals representing 18 unrelated kindreds had mutations in TGIF. Target exome capture panels and exome sequencing is in progress. Initial results confirm that the most common genes include SHH, SIX3, ZIC2, and FGFR1. De novo mutations in exons are the most common findings. DNA changes in evolutionarily conserved regions (ECRs), some of which have been shown to be gene-regulatory elements, are being evaluated.

Our group has elucidated many of the single genes and pathways for HPE and we are now initiating a search for other etiologies including unknown genes and enhancer regulatory elements. Initial functional studies of DNA changes in ECRs are in progress. Discovering new etiologies will have a significant impact on counseling affected families and will add scientific insight into molecular pathways involved in normal and abnormal brain development.

Muenke, M., Solomon, B.D., Odent, S. (eds): Holoprosencephaly. Am. J. Med. Genet. Part C: Seminars in Medical Genetics Vol. 154C, 2010.


Carina SchlebuschCarina Schlebusch was born in South Africa and completed her PhD under the supervision of Prof. Himla Soodyall at the University of the Witwatersrand, Johannesburg. Her thesis dealt with the history of southern African population groups and specifically with the population genetics of San and Khoekhoe groups. In 2009, she moved to Uppsala University, Sweden, where she started a Postdoc in the laboratory of Prof. Mattias Jakobsson. After her postdoc, she continued her research in African population history at Uppsala University and she is presently the PI of a research group that investigates human evolutionary history with a focus on Africa.

GEnETIC HISTORY OF AFRICA

In the last three decades, genetics played an increasingly important role in the inference of human history. Genetic studies provided conclusive information that helped to answer challenging questions, such as the “Out of Africa” migration of modern humans. Moreover, genetics helped to establish Africa as the birthplace of anatomically modern humans. The history of human populations in Africa is complex and includes various demographic events that influenced patterns of genetic variation across the continent. Several studies based on mitochondrial DNA, Y-chromosomes, autosomal markers and whole genomes contributed to unraveling the genetic sub-structure of African populations. Through these studies, it became evident the deepest population split among modern humans was between southern African Khoe-San populations and other African groups, while the central African Pygmy groups diverged subsequently from the common human lineage. Furthermore, it was shown that agriculture had a large influence on the distribution of current-day Africans and that West African agriculturist populations populated the whole of sub-Saharan Africa, replacing and/or assimilating former groups. Other farming groups from Northeast Africa, speaking Nilo-Saharan and Afro-Asiatic languages also expanded southwards and settled in East Africa, and perhaps as far as southern Africa, furthermore disrupting pre-existing population distributions. These later population movements complicate inferences regarding deep human history. With the increased availability of full genomic data from diverse African populations we will have more power to infer human demography and will especially try to address the complex aspects of deep human history. Furthermore, the first successful ancient DNA studies in Africa and the promise of many more African ancient DNA studies to come, will enable direct temporal comparisons – which will further contribute to unraveling deep human history on the African continent.

Suggested References• Campbell M, Hirbo J, Townsend J, Tishkoff SA (2014) The peopling of the African continent and the diaspora into

the new world. Current Opinion in Genetics & Development, vol 29, p120–132.• Gurdasani D, Carstensen T, Tekola-Ayele F, Pagani L, Tachmazidou I, Hatzikotoulas K, Karthikeyan S, Iles L,

Pollard MO, Choudhury A, Ritchie GR. The African genome variation project shapes medical genetics in Africa. Nature. 2015 Jan 15;517(7534):327-32.

• Lachance J, Vernot B, Elbers CC, Ferwerda B, Froment A, Bodo JM, et al, & Tishkoff SA (2012) Evolutionary history and adaptation from high-coverage whole-genome sequences of diverse African hunter-gatherers. Cell, 150(3), 457-469.

• Pickrell JK, and Reich D (2014) Toward a new history and geography of human genes informed by ancient DNA. Trends in Genetics, vol 30.9, p377-389.

• Schlebusch CM, Skoglund P, Sjödin P, Gattepaille LM, Hernandez D, Jay F, et al, & Jakobsson M (2012) Genomic variation in seven Khoe-San groups reveals adaptation and complex African history. Science, vol 338(6105), p374-379.

• Schlebusch CM, Malmström H, Günther T, Sjödin P, Coutinho A, Edlund H, Munters AR, Steyn M, Soodyall H, Lombard M, Jakobsson M. Ancient genomes from southern Africa pushes modern human divergence beyond 260,000 years ago. bioRxiv. 2017 Jan 1:145409.


Dr Glenda SobeyDr Glenda J Sobey is co-founder and head of the Ehlers-Danlos Syndrome National Diagnostic Service in the UK and Honorary Senior lecturer at the University of Sheffield. Dr Sobey is a Consultant Dermatologist with qualification in Clinical Genetics. She completed her specialist training at Groote Schuur Hospital.

Dr Sobey’s unit is responsible for the diagnosis of rare and atypical EDS. This includes specialist clinical evaluation, skin biopsy with electron microscopy and molecular genetic testing for all known EDS genes in the Sheffield laboratory.

This service acts as a full clinical genetics service including genetic counselling. In addition her team advises on and coordinates management of this group of patients. Together with cardiology colleagues she runs a specialist EDS cardiology clinic for patients at risk of blood vessel rupture.

Dr Sobey has an active role in teaching and lectures nationally and internationally. She has published widely. She is particularly interested in promoting early diagnosis in rare disease to allow optimal outcome for patients and families.

EHlERS DAnlOS SYnDROME - A nATIOnAl DIAGnOSTIC SERVICE

The term Ehlers-Danlos Syndrome (EDS) refers to a group of inherited connective tissue disorders. In many subtypes the genetic basis is now known. The skin, joints, blood vessels and hollow organs can all be affected with consequences varying from mild features to severe life threatening events. The accurate diagnosis of EDS, can allow specific management, family screening and prenatal diagnosis.

The development of the EDS National Diagnostic Service serves as a paradigm for service development to meet the needs of patients with rare disesase.


Jim WilsonResearch in Prof Wilson’s group focuses on the genetic architecture of complex traits and the identification of genetic variants influencing quantitative risk factors for common diseases such as obesity and diabetes.

He is particularly interested in high kinship isolate populations which have increased utility for rare variant discovery and leads a number of population-based studies in Scotland which have contributed to the discovery of >1000 new genome-wide associations. His major research interest is in homozygosity – he leads an international consortium of >100 cohort studies (ROHgen) which seeks to understand the effect of inbreeding depression on complex traits. He also steers a second consortium, Ygen, which is assessing the influence of Y chromosome variation on complex traits.

Lifespan is a growing area of interest, being in various ways the ultimate complex trait – the LifeGen consortium is discovering variants influencing length of life. Other research themes include the genetics of fat distribution and Multiple Sclerosis. A final strand of activity is in population genetics, particularly focussed on the genetic history of the British Isles. Prof Wilson regularly contributes to documentaries explaining genetics to the public.

SEx-SPECIFIC InBREEDInG DEPRESSIOn In HUMAnS

Inbreeding depression - reduced evolutionary fitness in the offspring of related parents - is observed in many plant and animal species, and is thought to have played an important role in the evolution of outcrossing mating systems. Here, in a analysis of over one million individuals, we show that increased autozygosity, caused by parental relatedness, has a statistically significant effect on 11 of 42 human complex traits analysed. For the first time in a genetic study, we show that increased autozygosity reduces reproductive success in humans, as well as influencing medically important traits associated with survival and reproduction. In addition, we observe that, for many traits, the effect of inbreeding is significantly greater in men than in women, consistent with observations in other species where the more heavily selected sex suffers greater inbreeding depression. We present evidence that the observed effects are caused by genetic factors and not by unobserved environmental confounders. In particular, the effect of autozygosity is consistent across diverse populations, and a linear relationship is observed between autozygosity and phenotypic changes. The other things you requested are below.


Ingrid WinshipProfessor Ingrid Winship is the Executive Director of Research for Melbourne Health and the Chair of Adult Clinical Genetics at The University of Melbourne. She has 30 years’ experience in Clinical Genetics, having trained in Cape Town. After establishing comprehensive genetic services in New Zealand, she now has a leading role in genetics in Australia. Her work includes gene discovery and clinical research, service development and translational research, developing new models of genetic services especially for adult patients with inherited predisposition to cancer. She is a member of the Australian Health Ethics Committee, and served for 6 years until its completion on the NHMRC Human Genetic Advisory Committee.

PRECISIOn MEDICInE: REDUCInG THE BURDEn OF DISEASE BY PREVEnTIOn THROUGH GEnETICS AnD GEnOMICS

An understanding of the role of genetics and genomics in disease can help to reduce the burden of disease through prevention, early detection and optimisation of management and monitoring. This is well illustrated in cancer; knowledge that underpins genomics in heritable predisposition, tumorigenesis, progression of disease and response to management will provide the basis for the implementation of personalised or precision medicine. Genomic variation contributes to risk estimation, allowing for risk stratification and consequent optimisation of cancer prevention through rational screening. Combining the knowledge of biology, with surveillance and therapeutics, including pharmacogenomics, will provide the desired advances in knowledge and the evidence required for precision health care.

Precision medicine through prevention extends beyond cancer. It is of value to individuals and their families to identify mutations in predisposition genes in multiple adult onset disease disorders such as cardiomyopathy or renal failure. Early intervention may have markedly improved outcomes. Polygenic risks scores will allow better risk estimation in the community, with the allocation of resources to the areas of greatest need. The effective application of pharmacogenomics will reduce adverse events of medication, while efficacy will increase, using the right drug (or dose) for the right genotype.

Holistic use of genetic and genomic technologies, with the supporting informatics and clinical evidence, and attention to the ethical, cultural, spiritual and legal issues, will help to create a respectful, efficient and sustainable approach to healthcare for the future.


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SOCIAlISInG THE GEnOME

Anna Middleton

Sequencing technologies are transforming medicine in the UK. However recent research has discovered a major stumbling block: only a minority of the British public understands and can relate to even the simplest of terms used in genetics. Because this problem could threaten to blunt the impact of genetics-based medicine – the Socialising the Genome project was designed. Anna will discuss her research and endeavours to turn genomics from (what is for many) an anti-social concept (‘I won’t understand it’, ‘I didn’t do science at school’) to a more social concept. She will explore her work with advertising experts, to create a series of evidence-based animations to explore different ways to help the general public start conversations about genetics (e.g. trying out socially acceptable words like ‘glitch’ in replacement for ‘variant’). She will also discuss and share the films she has created to bring the public to her research about DNA and Big Data. Being able to contribute to current discussions about genomics requires researchers to make the dialogue accessible, even using the simplest of genomics terminology has the capacity to alienate the very people they want to engage. ‘Socialsing the Genome’ is a frame of mind that permeates Anna’s approach to research, it is grounded in her clinical experience of working directly with families in the NHS as a genetic counsellor.

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CHIlDREn WITH OCUlOCUTAnEOUS AlBInISM: CHAllEnGES AnD MAnAGEMEnT

Jennifer KrombergUniversity of the Witwatersrand and NHLS, Johannesburg, South Africa

In South Africa 1 in 4-5000 people have albinism (OCA). This paper aims to report on the available data from 5 studies on affected children and suggest management strategies.

(i). Longitudinal studies on maternal-infant interaction showed mothers (N=37) were reluctant to hold and breast-feed their infants with OCA and maternal-infant attachment was delayed (compared with 37 matched controls). Infants were slower to sit and crawl. Mothers require counselling regarding OCA perinatally and children need stimulation programmes. (ii). Intellectual maturity and body boundary characteristics were tested in 28 children with OCA (mean age 11 years) and 28 matched controls. Affected children were more intellectually mature, but had difficult y creating a self-image, suggesting negative self-evaluation. (iii). Adjustment and attitudes towards OCA were investigated in 35 teenagers with OCA (mean age 17 years) and 35 matched controls. Those with OCA were quite well adjusted, but had physical problems. Attitudes were reasonably positive, but belief in the death myth reduced full acceptance. Affected children need counselling and the public need awareness programmes. (iv). Precancerous lesions were found in 6% of affected children aged 0-9 years and in 13% of those aged 10-19 years; lesions increased with age and were commonly found on the head and cheek. Sunscreen cream, long sleeved cotton clothing, hats and regular skin assessment and care are required from early childhood for life. (v). Visual defects (e.g. nystagmus, strabismus, myopia) occur in every affected child and they require regular assessment and treatment from the first year of life onwards. Prescription spectacles, dark glasses, and seating at the front of the class-room and away from the glare, helps.

In conclusion, affected children should be better managed from early childhood onwards, in order to prevent the side-effects of OCA from limiting their potential and reducing their quality of life.

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THE COMPlExITIES OF GEnETIC COUnSEllInG FOR nOnSYnDROMIC HEARInG IMPAIRMEnT In THE SOUTH AFRICAn COnTExT

Sinead Amber Ross1, nakita laing2, Sumaya Mall3, Ambroise Wonkam1

1Division of Human Genetics, University of Cape, Cape Town, Western Cape, South Africa, 2Groote Schuur Hospital, Cape Town, Western Cape, South Africa, 3Department of Psychiatry and Mental Health, University of Cape Town, Cape Town,

Western Cape, South Africa

Background: Hearing impairment (HI), is a significant public health issue particularly in the developing world. Disabling HI affects 6 in 1000 live births in South Africa (SA) with genetic aetiology accounting for 50% of prelingual HI. Context is essential in understanding the role that HI plays in the lives of those affected. In SA there is limited infrastructure in place for those with HI and many specialised services are not country-wide. Genetic counselling for hereditary HI remains underutilised, and the complexities in providing supportive as well as educational care to these families, needs to be understood.

Objective: To explore parents’ experiences of having a child with nonsyndromic HI in a selected setting in Cape Town and to investigate the role of genetic counselling services for this population.

Methods: Qualitative research methodology was employed in this study. Following collection of socio-demographic information using a questionnaire, semi-structured interviews were conducted with eleven parents of children who attended a deaf school in Cape Town, or who had previously been seen at the genetics clinic at Red Cross War Memorial Children’s Hospital. Thematic analysis was performed.

Results: Data related to the difficulties and burdens experienced by these parents were explored. It was evident from the parents’ accounts that the practicalities of raising a deaf child were immense. Language and communication barriers as the most apparent, but also financial difficulties and access to schooling and health care. Parents often needed to make sacrifices for their child which included forgoing work so that they could attend multiple clinic visits, as well as the emotional sacrifices and burdens of caring for a child with specialised needs without means of support. Parents in this study found that they had the added worry of needing to provide their deaf child with protection as their HI made them especially vulnerable.

Conclusion: South Africa is a unique setting and it is important that genetic health care professionals working in this context understand the experiences and perspectives of parents of children with hereditary HI, with the aim of providing appropriate genetic counselling that meets the specialised needs of these families.

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GEnETIC COUnSEllInG In CARDIO-GEnETIC RESEARCH: A CASE REPORT OF CDH2

nakita laing1, Sarah Kraus2, Gasnat Shaboodien2, Maryam Fish2, Bongani Mayosi2

1Groote Schuur Hospital, Cape Town, South Africa, 2University of Cape Town, Cape Town, South Africa

Introduction: Genetic mutations in cadherin-2 (CDH2) have recently been described as a novel cause of Arrhythmogenic right ventricular cardiomyopathy (ARVC) in two South African families and by a further international group. ARVC is a heterogenous autosomal dominantly inherited condition which increases the risk for sudden cardiac death (SCD) in young individuals. We report on a large multigenerational family, clinically affected by ARVC, which was key to the identification of this novel cause of ARVC. The case report focuses mainly on the role of and challenges faced by genetic counsellors in the research setting of cardiovascular genetics.

Case description: The family (ACM2) was initially referred in 1996 and several family members were diagnosed as being clinically affected with ARVC based on the 1994 Task force criteria. A genetic counsellor became involved with the family in 2012 after there was a possible molecular cause identified on initial testing and analysis of the data. The process of genetic counselling in this research setting included telephonic discussions and arrangement of a family meeting to discuss the condition, the research progress, re-sampling and extension of the family history. Facilitation of phenotyping of key family members also occurred. As early diagnosis and treatment of ARVC is key to the management of affected individuals, pedigree extension and cascade screening of distant relatives at risk for the condition was performed. They were approached and offered medical screening for ARVC as well as the opportunity to participate in the genetic research. Following review of the molecular results and reclassification of individuals according to the updated 2010 Task force criteria, the phenotypic and genotypic information was integrated; allowing the identification of the novel CDH2 gene mutation responsible in ACM2. Translation of these research findings via telephonic result delivery has been performed and the individuals concerned have shown deep appreciation to finally understanding the cause of the condition in the family. In addition this finding has allowed presymptomatic testing in at risk individuals.

Discussion: This case highlights the role of the genetic counsellor specifically in the maintenance of open communication and relationships with the research team allowing feedback of research progress, updating of patient information, ethical consideration of cascade screening and result delivery. Ongoing facilitation of presymptomatic testing and genetic counselling in this family allows the possibility to prevent SCD in newly identified at risk individuals.

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PERCEPTIOnS OF HEAlTH RElATED QUAlITY OF lIFE AMOnG ADUlTS lIVInG WITH SICKlE CEll DISEASE In CAPE TOWn, SOUTH AFRICA

Clair Engelbrecht1, Ambroise Wonkam1, nakita laing1, Sumaya Mall2

1University of Cape Town, Cape Town, South Africa, 2University of the Witwatersrand, Johannesburg, South Africa

Sickle cell disease (SCD) is a chronic, heritable haemoglobinopathy highly prevalent in Sub-Saharan Africa. Haemoglobinopathies alone are estimated to cause a disease burden comparable to all communicable diseases collectively. Those affected with SCD suffer from debilitating health issues and require frequent hospitalisation. Affected individuals don’t only require medical treatment but also psychosocial support to help them with the consequences of a chronic illness well into adulthood.

Understanding health related quality of life (HRQL) is important to be able to provide adequate medical treatment and therapeutic, counselling and support options relevant to the patients. Very little HRQL research has been carried out in an African setting indicating an urgent unmet need. Much research looking at HRQL in SCD uses validated patient reported outcome (PRO) instruments. Currently there are no SCD specific PRO instruments validated for African populations where SCD is highly prevalent. To achieve this, it is important to qualitatively determine potential issues regarding impact of SCD on African patients before quantitative PRO tools can be adapted and implemented.

To meet this need, an in-depth qualitative research approach was used whereby several interviews were conducted with consenting adults living with SCD in Cape Town. The data was collected via recorders and transcribed by the researcher. The data was analysed using the framework approach.

Themes emerging from the data within this population indicate that SCD can have a significant negative impact on HRQL in adults. Career opportunities, relationships and perceptions of oneself have all emerged from the data to be negatively affected by having to live with SCD. Issues specific to African SCD patients are appearing to emerge in the form of healthcare, where emerging inadequacies within the healthcare system need to be addressed.

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BlACK SOUTH AFRICAn WOMEn’S PERSPECTIVES On THE IMPACT OF HAVInG A BABY WITH A GEnETIC DISORDER On THEIR SPOUSAl RElATIOnSHIP

Tabitha Haw1,2, Sasha Henriques1,2

1National Health Laboratory Service, Johannesburg, South Africa, 2University of the Witwatersrand, Johannesburg, South Africa

There is a large body of research exploring the impact that a baby with a genetic disorder can have on family functioning and spousal relationships. This research has been done almost exclusively using white subjects in the USA and UK, and most of the participants in these studies have been well resourced and in stable relationships. There is a scarcity of information on this subject in families and partnerships from other ethnic groups and parts of the world. This study examines the impact that having a baby with a genetic condition has on the spousal relationship from the perspective of black South African women in state healthcare. Mothers who have children with genetic disorders seen at the Genetic Counselling Clinics at Charlotte Maxeke Johannesburg Academic Hospital (CMJA) and Chris Hani Baragwanath (CHB) Hospital for genetic counselling were selected to take part in the study. The data was collected through semi-structured interviews lasting about 20-30 minutes. Interpretative phenomenological analysis (IPA) will be used to study each participant’s personal experiences in detail and explore how they make sense of their experiences. The information from this research project will be important and significant because the spousal relationship is central to the functioning of a family. Understanding the impact that having a child with a genetic disorder has on this relationship can assist genetic counsellors to provide more focused and empathic support for women and couples in this situation in South Africa.


MICROTEACHInG CAn BE An EFFICIEnT TECHnIQUE TO TRAIn THE GEnETICS EDUCATOR

Chantel van WykUniversity of the Free State, Bloemfontein, South Africa

Introduction Microteaching is an educational technique used to prepare educators to gradually obtain relevant pedagogic competencies. The technique uses real-time teaching experiences and offers improved self-awareness, confidence in lecturing and the ability to effectively reflect on teaching (Donnelly & Fitzmaurice 2011:1). At the University of the Free State newly appointed educators reflected that participating in a microteaching activity initially made them feel apprehensive, in terms of ‘being evaluated’. However, on completion of the activity they concluded that being evaluated in microteaching added value, as they subsequently felt more confident as educators and more competent to implement newly acquired teaching skills (Van Wyk & Kridiotis 2015). Objective To present guidelines on how to use microteaching to train the genetics educator.

Methods Research conducted on newly appointed health professions educators who participated in a microteaching activity was used to formulate guidelines on how to effectively use microteaching to train the genetics educator. The microteaching activity was self-evaluated, peer evaluated and also expert evaluated by means of a rubric.

Results Microteaching is applied in a sequential manner and several key role players are involved. The steps of this technique will be outlined. The significance of this technique is that a genetics educator, novice as well as experienced, may use the technique to practically depict their teaching abilities in a constructive educational environment which offers an interactive opportunity to reflect on their own skills (with a view to improvement) and to gain insight from the experience of peers and educational experts. Research has shown that predominantly practical and interactive learning sessions (to learn by doing and/or experiencing) are favoured by the adult learner.

Conclusion Using microteaching to train genetic educators will not only offer the educator the opportunity to enhance his/her teaching skills but contribute to an educator’s positive attitude towards teaching. The need for faculty development to enhance pedagogical content knowledge in the field of genetics is emphasised. This provides an opportunity for ongoing discussions and further research.


PRECISIOn MEDICInE: REDUCInG THE BURDEn OF DISEASE BY PREVEnTIOn THROUGH GEnETICS AnD GEnOMICS.

Ingrid Winship

An understanding of the role of genetics and genomics in disease can help to reduce the burden of disease through prevention, early detection and optimisation of management and monitoring. This is well illustrated in cancer; knowledge that underpins genomics in heritable predisposition, tumorigenesis, progression of disease and response to management will provide the basis for the implementation of personalised or precision medicine. Genomic variation contributes to risk estimation, allowing for risk stratification and consequent optimisation of cancer prevention through rational screening. Combining the knowledge of biology, with surveillance and therapeutics, including pharmacogenomics, will provide the desired advances in knowledge and the evidence required for precision health care.

Precision medicine through prevention extends beyond cancer. It is of value to individuals and their families to identify mutations in predisposition genes in multiple adult onset disease disorders such as cardiomyopathy or renal failure. Early intervention may have markedly improved outcomes. Polygenic risks scores will allow better risk estimation in the community, with the allocation of resources to the areas of greatest need. The effective application of pharmacogenomics will reduce adverse events of medication, while efficacy will increase, using the right drug (or dose) for the right genotype.

Holistic use of genetic and genomic technologies, with the supporting informatics and clinical evidence, and attention to the ethical, cultural, spiritual and legal issues, will help to create a respectful, efficient and sustainable approach to healthcare for the future.


InDICATIOnS FOR TESTInG AnD CHROMOSOME AnEUPlOIDY PICK-UP RATES In PATIEnTS REFERRED FOR nOn-InVASIVE PREnATAl TESTInG (nIPT) In SOUTH

AFRICA

Jaysen Knezovich1,2, Tamaryn Hughes2

1University of the Witwatersrand, Johannesburg, Gauteng, South Africa, 2Genesis Genetics, Johannesburg, Gauteng, South Africa

Introduction. Monitoring the health of an on-going pregnancy may involve screening and/or diagnostic tests. Screening tests are generally regarded as non-invasive (and hence safe), while diagnostic tests are regarded as invasive (which carry certain risks). Conventional screening typically involves screening blood serum markers in conjunction with ultrasound, followed by invasive genetic diagnostic testing for positive screen results. Invasive procedures are associated with risk related to miscarriage. Non-invasive prenatal testing (NIPT) is relatively new and revolutionary screening tool which quantifies circulating foetal cell-free DNA in a pregnant woman, from a maternal blood sample. NIPT aims to identify the presence (or absence) of viable chromosomal aneuploidies, such as Trisomy 21, with high accuracy (>99%). This study aimed to assess the indications for NIPT testing and associated chromosomal aneuploidy pick-up rate for each.

Methods. A total of 1,924 patients referred for NIPT in South Africa, were assessed in terms of indication for testing and pick-up of a chromosomal abnormality. NIPT was undertaken using Illumina’s verifi® technology, which screens for trisomies of Chromosomes 13, 18, 21 and sex chromosome aneuploidies.

Results. Indications for testing included abnormal ultrasound (7%), advanced maternal age (>35 years old, 44%), history of an affected pregnancy (2%), multiple indications (6%), patient concern (26%), and positive serum screen (14%). The total pick-up rate across all indications was 4%, and that for each indication was as follows: abnormal ultrasound (6%), advanced maternal age (3%), history of an affected pregnancy (2%), multiple indications (7%), patient concern (2%), and positive serum screen (5%).

Conclusion. While almost half of patients referred for NIPT are of advanced maternal age (44%), the pick-up rate of a chromosomal abnormality is one of the lowest (3%). Pick-up rates are the highest in patients with multiple indications (7%), abnormal ultrasound (6%), and a positive serum screen (5%). While the overall aneuploidy pick-rate using NIPT is relatively low (4%), implementing NIPT as a screening strategy can lead to a decrease the number of invasive tests undertaken, and thus a decrease in procedure-related miscarriages.


CHROMOSOMAl AnEUPlOIDY RATES AnD DISTRIBUTIOn In EMBRYOS GEnERATED In THE SOUTH AFRICAn FERTIlITY SETTInG

Jaysen Knezovich1,2, Kajel Somaroo2

1University of the Witwatersrand, Johannesburg, Gauteng, South Africa, 2Genesis Genetics, Johannesburg, Gauteng, South Africa

Introduction. Preimplantation genetic screening (PGS) is the testing of early stage human embryos for chromosomal aneuploidies. PGS makes use of a biopsy taken from an embryo generated in the fertility setting, to determine chromosome number (ploidy) status of each embryo. Ploidy status assists embryologists with the selection of embryos that are chromosomally normal, which are transferred to a patient’s uterus. Advancing maternal age significantly increases aneuploidy rates in embryos. This study aimed to (1) quantify embryo aneuploidy rates, stratified by maternal age, and (2) assess the distribution of observed aneuploidies. Array comparative genome hybridisation (aCGH) based PGS allows for comprehensive chromosome screening of chromosomes 1-22, X and Y.

Methods. aCGH PGS was undertaken on 3,552 embryos generated from 890 IVF cycles in 14 South African fertility clinics across various maternal age groups. Aneuploidy rates were calculated for maternal ages, ranging from 30 to 45 years old, and that of fertility cycles that made use of donor eggs from young donors. The aneuploidy rate was also quantified for each chromosome.

Results. The average aneuploidy rate per maternal age group was as follows: 30-34 years, 61.7%; 35-39 years, 67.6%; >39 years, 78.8%. Interestingly, an aneuploidy rate of 68.22% was observed in egg donor cycles. Aneuploidies were observed for all chromosomes, with almost equal frequency. The most frequent aneuploidies involved Chromosome 16 and 22, accounting for 3.3% and 2.9% of all aneuploidies, respectively.

Conclusion. Expectedly, aneuploidy rates increased with increasing maternal age. Aneuploidy rates are relatively high, even in younger patient cohorts (30-34 years old). Unexpectedly, egg donor cycle aneuploidy rates were comparable to those of maternal age group 35-39 years old. Aneuploidies involve all chromosomes, with relatively equal frequency. Aneuploidies of Chromosomes 16 and 22, account for the largest proportion of aneuploidies. This is supported by evidence that these chromosomes are the most frequently occurring aneuploidies in first trimester miscarriages. PGS is a valuable genetic tool to screen out aneuploid embryos in the fertility setting, across all age groups (including cycles making use of donor eggs), and improve clinical outcomes.


ASSESSMEnT OF GEnETIC COUnSEllInG SERVICES AnD GEnETIC TESTInG UPTAKE In A PREnATAl SETTInG

Katryn Fourie, Mike Urban, Mardelle SchoemanUniversity of Stellenbosch, Cape Town, South Africa

In studies of women at high risk for Down syndrome, reported uptake of invasive testing is 40-86%. We assessed uptake by indication at Tygerberg Hospital Prenatal Diagnosis Clinic. Consecutive genetic counselling clinic records were retrospectively analysed for the period 2010 to 2016.

• Of 5424 cases included, 1468 (27.0%) accepted invasive testing, which was offered for several indications. By indication, uptake of invasive testing was

• 297/2061 (14.4%) for women screening high risk for Down syndrome based on advanced maternal age (AMA) alone.

• 280/1080 (25.9%) for women who were AMA but also had sonographic ‘soft markers’ for Down syndrome on 1st or 2nd trimester scan.

• 351/870 (40.3%) for women who were not AMA but screened high risk for Down syndrome based on 1st or 2nd trimester sonographic markers.

• 540/1413 (38.2%) for women with a fetal anomaly (FA).

Compared to the ‘AMA alone’ group, all other groups had significantly higher uptake rates (P<0.001 in all cases), with uptake being similar between the FA and the sonographic soft marker groups (P=0.31).Uptake over time reduced from 32.5% in 2012 to 23.8% in 2016 (chi square for trend <0.001), and a similar uptake was noted for each indication. Information regarding women’s reasons to decline invasive testing was prospectively recorded from a dropdown list, with data available for 2385 (74.8%) of 3187 AMA cases. The most commonly cited reason was acceptance of a child with Down syndrome, which increased from 24% in 2010 to 55% in 2016.

Several possible explanations for the decline in uptake were considered, including changes in genetic services or variations in the prenatal screening protocol. The most likely reason is a combination of improved genetic services, resulting in more informed decision making; and increased acceptance of Down syndrome as a condition. The findings will be used to optimise prenatal services in the TBH area.


ExPlORInG THE DECISIOn-MAKInG PROCESS OF WOMEn OFFERED TERMInATIOn OF PREGnAnCY FOR A SERIOUS COnGEnITAl ABnORMAlITY.

Malebo Malope1, Tina-Marie Wessels1, Chantal Stewart1,2, Karen Fieggen1,2

1University of Cape Town, Cape Town, Western Cape, South Africa, 2Groote Schuur Hospital, Cape Town, Western Cape, South Africa

Background: A weekly pregnancy counselling clinic is held in conjunction with foetal medicine experts at Groote Schuur Hospital for women with pregnancies complicated by foetal anomalies. Those in whom serious congenital abnormalities with a poor prognosis was diagnosed, may be offered termination of pregnancy (TOP). The experiences and decision-making process of these women in this clinic is poorly understood and this projects aims to explore these women’s experiences and what influences their decision making regarding TOP.

Methods: Ethics approval was obtained from the Human Research Ethics Committee at the University of Cape Town. The women were identified using the Division of Human Genetics pregnancy counselling database. They were initially contacted by either the clinician or the counsellor who had previously counselled them to discuss participation. Those agreeing to participate were contacted by the researcher. The data was collected in the form of face-to-face interviews ranging from 30 minutes to an hour in length. The interviews were recorded and transcribed verbatim. Data was analysed using a thematic data analysis approach.

Results: Preliminary results indicate that there are multiple considerations for these women when contemplating the option of terminating their pregnancies. Religion played a role, but so did the overall experience of care and information given to the patients by the clinic. Support from family, their perception of the stigma attached to having a child with a disability and/or stigma against termination played a role in who they informed about their child’s condition. Another theme that emerged is the women’s need to attach meaning to why this happened to them. This was not necessarily based only on the medical information given but often on how they believed this affected the family unit.

Conclusion: The decision making process for women considering termination of pregnancy for a serious congenital abnormality is multifaceted. By exploring some of these experiences in depth, this study will assist in providing better supportive and counselling services for women in similar circumstances in future.


An EVAlUATIOn OF PREIMPlAnTATIOn GEnETIC DIAGnOSIS OUTCOMES In JOHAnnESBURG, SOUTH AFRICA

Bianca Carzis1,2, Tasha Wainstein1,2, Amanda Krause1,2, Lawrence Gobetz3

1University of the Witwatersrand, Johannesburg, South Africa, 2National Health Laboratory Services, Johannesburg, South Africa, 3Vitalab, Johannesburg, South Africa

Preimplantation genetic diagnosis (PGD) is a process that involves testing embryos that were created using artificial reproductive techniques (ART) for genetic conditions before being transferred to a woman’s uterus for implantation. For couples who are at risk of having a child affected with a genetic condition, PGD provides an alternative option to prenatal testing and has the potential to avoid an unwanted termination of pregnancy. In Johannesburg, South Africa, the Division of Human Genetics at the National Health Laboratory Service (NHLS) and the University of the Witwatersrand (Wits) in collaboration with Genesis Genetics and Vitalab Fertility Clinic has offered PGD services to private patients for ten years. To date, no audit of this service has ever taken place. The aim of this study is to determine the number and nature of PGD cases that have been seen through the Division of Human Genetics (NHLS/Wits) and assess the outcomes at various stages of the PGD process. This study is a retrospective case review involving an audit of patients’ genetic counselling, fertility and PGD records. Information regarding family and obstetric history, the number of IVF cycles undertaken, the number of embryos tested and transferred, pregnancy outcomes, as well as the total time taken to complete the PGD process will be analysed quantitatively. A cost analysis of the PGD process will also be included. IVF outcomes at various stages of the processes will be evaluated. Each IVF cycle will be analysed separately and averages will be reported for each couple. Average outcomes for the entire study sample will also be reported. Preliminary results from data collected thus far show that 31 patients have been seen through the department for PGD-related genetic counselling from 2006-2016. The majority of these patients were Caucasian. Haemoglobinopathies, neuromuscular and metabolic conditions were the most prevalent conditions in this sample, and more generally, autosomal recessive conditions were the most common. The results obtained from this study will enable genetic counsellors and other healthcare professionals involved in the PGD process to provide patients with more accurate information regarding PGD outcomes and costs in South Africa. This will allow patients to make informed decisions when considering PGD as a reproductive option.

(Expect to have results by latest July)


GEnETICS AnD GEnOMICS OF HOlOPROSEnCEPHAlY

Maximilian Muenke1, Paul S. Kruszka1, Benjamin D. Solomon1,2, Donald W. Hadley1, Rachel A. Hart1, Yonit Addissie1, Yu Abe1, Ariel F. Martinez1, Sung-Kook Hong1,

Ping Hu1, Erich Roessler1 and Clinicians around the World1Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA;

2GeneDx, Gaithersburg, MD, USA (M.M. contact: [email protected])

Holoprosencephaly (HPE) is the most common anomaly of the developing forebrain with an incidence of 1 in 250 embryos and 1 in 10,000 live-born infants. HPE has a wide continuum of severity and most individuals show varying degrees of developmental and intellectual disabilities (for a detailed review see Muenke et al. 2010). Both, genetic mutations and environmental exposures have been found to be responsible for HPE. We and others have discovered over a dozen genes associated with HPE and illuminated a number of key molecular pathways involved in human early embryonic development. However, these genes together only account for 20 % of documented HPE cases which emphasizes the need for further investigation into the etiology of HPE.

Approximately 2000 individuals with HPE and their parents (HPE) have been enrolled in our study: 396 individuals representing 157 unrelated kindreds had deleterious mutations (defined as non-sense, deletions, slice site, or missense with deleterious zebrafish assay) in SHH, 157 individuals from 119 unrelated kindreds had mutations in ZIC2, 138 individuals representing 77 unrelated kindreds had mutations in SIX3, and 34 individuals representing 18 unrelated kindreds had mutations in TGIF. Target exome capture panels and exome sequencing is in progress. Initial results confirm that the most common genes include SHH, SIX3, ZIC2, and FGFR1. De novo mutations in exons are the most common findings. DNA changes in evolutionarily conserved regions (ECRs), some of which have been shown to be gene-regulatory elements, are being evaluated.

Our group has elucidated many of the single genes and pathways for HPE and we are now initiating a search for other etiologies including unknown genes and enhancer regulatory elements. Initial functional studies of DNA changes in ECRs are in progress. Discovering new etiologies will have a significant impact on counseling affected families and will add scientific insight into molecular pathways involved in normal and abnormal brain development.

Muenke, M., Solomon, B.D., Odent, S. (eds): Holoprosencephaly. Am. J. Med. Genet. Part C: Seminars in Medical Genetics Vol. 154C, 2010.


MODEllED EPIDEMIOlOGICAl DATA FOR COnGEnITAl DISORDERS In SOUTH AFRICA

Helen Malherbe1, Colleen Aldous1, Arnold Christianson2, Matthew Darlison3, Bernadette Modell3

1School of Clinical Medicine, College of Health Sciences, University of KwaZulu Natal, KwaZulu Natal, South Africa, 2Wits Centre for Ethics (WiCE), University of the Witwatersrand, Gauteng, South Africa, 3WHO Collaborating Centre for Community

Genetics, Centre for Health Informatics and Multiprofessional Education (CHIME), University College London, London, UK

Observed, empiric data related to congenital disorders (CDs) are necessary to obtain political commitment and funding to develop targeted medical genetic services. In the absence of empiric data, modelling is a relevant tool for estimating expected numbers of CDs until surveillance and monitoring systems are adequately developed. In South Africa (SA), CDs are underreported by 98%, highlighting the need for such modelled estimates. This underreporting, combined with capacity shortages leading to misdiagnosis, non-diagnosis and the mis-classification of CD related deaths, contributes to an inaccurate evaluation and underestimate of the contribution of CDs to the disease burden. This results in a lack of recognition for this health care issue and inadequate services for their care and prevention.

The Modell Global Database of Congenital Disorders (MGDb) modelling methods were used to quantify the CD burden of disease in SA. The MGDb uses birth prevalence data from well-established surveillance systems with local demographic data. Baseline country estimates for specific categories of endogenous CDs were generated in the absence of care for 2012. The 2012 actual birth prevalence (factoring in available care) was then estimated using the MGDb approach to evaluate the effect of present interventions compared with baseline estimates. Access to relevant health services, and so the impact of interventions, was quantified using the infant mortality rate (IMR) as a proxy.

Baseline estimates for 2012 indicated a birth prevalence of 30.5 affected births per 1 000 live births decreased to 29.4 per 1 000 with access to services estimated at 30%. This study highlights the utility of modelled data in profiling the disease burden of CDs in SA, and the impact of medical genetic services in reducing mortality and improving the quality of life of those affected.


HUnTInGTOn DISEASE In SOUTH AFRICA - WHERE ARE WE?

Amanda Krause1, David Anderson2, Fiona Baine2

1Division of Human Genetics, NHLS and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa, 2Division of Human Genetics, School of Pathology, Faculty of Health Sciences, University of the

Witwatersrand, Johannesburg, South Africa

Huntington disease (HD) is an inherited, progressive neurodegenerative disease, caused by a trinucleotide repeat expansion in the HTT gene. An HD phenocopy (HDL2), due to a trinucleotide expansion in the JPH3 gene, accounts for one third of confirmed HD diagnoses in South Africa, the highest reported number worldwide. Only 69 cases of HDL2 have been described in the literature, all with African ancestry.

The clinical phenotype of HDL2 is reported to be broadly similar to HD but some differences have been proposed, based largely on single or small case study observations. A study to systematically characterize the clinical phenotype of HDL2 from a neurological, neuropsychological, haematological and radiological perspective; and to compare it to HD is ongoing. Preliminary data on 22 patients (13 HD and 9 HDL2) suggest that the eye signs are indistinguishable from HD, suggesting that oculomotor signs are not a distinguishing feature of HDL2 as has been proposed in early reports. There was no significant difference in the total score between the two diseases or in any median sub-score parameters of ocular pursuit, saccade initiation or saccade velocity. Early reports suggested that the presence of acanthocytes in the peripheral blood smear might distinguish patients with HDL2 from those with HD. Preliminary results on South African cases suggest that this is not the case.

Further, at a genetic level approximately 30-50% of patients referred for HD diagnostic testing test negative for both HD and HDL2, despite some having suggestive clinical features. A total of 104 individuals of African ancestry individuals were screened for pathogenic expansions in genes associated with other dynamic repeat disorders -TBP (SCA17), ATN1 (DRPLA), C9orf72 gene, ATXN2 (SCA2) and ATXN7(SCA7). A single expanded triplet was identified in the ATXN2 gene confirming a diagnosis of SCA2; this equates to ~1% in this sample of South African patients. Targeted sequencing using a custom panel of selected genes associated with HD-like disorders is in progress to determine whether other HD phenocopies are prevalent.

Further sequencing analysis is in progress to characterise the JPH3 and HTT repeats in African individuals. These data have important significance for diagnosis and management of HD and HDL2.


GEnETICS OF nOn SYnDROMIC HEARInG lOSS In AFRICA

Ambroise Wonkam


FAnCOnI AnAEMIA – PAST, PRESEnT AnD FUTURE In A SOUTH AFRICAn COnTExT

Candice Feben1,2, Tasha Wainstein2, Amanda Krause1,2

1National Health Laboratory Service, Braamfontein, Johannesburg, South Africa, 2The University of the Witwatersrand, Johannesburg, South Africa

Fanconi anaemia is a rare genetic condition characterised cytogenetically by spontaneous and induced chromosome breakage and resulting clinically in congenital malformations, haematological disease and childhood onset bone marrow aplasia. More than 21 genes, functioning in a highly complex cell cycle pathway, have been discovered in the pathogenesis of the condition since it was originally described in 1962. In South Africa, founder mutations in two FA genes have resulted in a higher incidence of the condition in Black (FANCG) and Afrikaans (FANCA) individuals. Genotype-phenotype correlation studies in these population subgroups have highlighted differences in the presentation of the condition between these populations and have led to suggested management guidelines for appropriate care. However, despite a well described clinical phenotype, recognition of the disease in South Africa and internationally is considered poor with most cases diagnosed only when severe bone marrow disease manifests. The reasons for the under-recognition and under-diagnosis in our local setting remain unclear, but it is apparent from the discrepancy between calculated birth rates in founder populations and genetic test referrals that less than 10% of patients with FA have molecular confirmation of their disease. The personal and familial repercussions of this are manifold. Owing to the prevalence of the founder mutations, molecular testing for FA in South Africa currently only evaluates the FANCG and FANCA genes by targeted mutation analysis. Evolution of next generation sequencing technologies and the implementation of genetic panel testing internationally has allowed for collaborative research efforts and the subsequent detection of mutations in other FA genes in South African patients. Of specific interest is the diagnosis of two cases of FA caused by bi-allelic BRCA2 (FANCD1) mutations. These cases highlight the link between familial cancer and FA. Mutations in other rarer FANC genes are also currently being investigated. The questions raised by the research findings are “How many cases of FA are missed as we do not offer comprehensive testing in SA?” and “If next generation sequencing panels were available locally would we be addressing the diagnostic gap that currently exists for FA?” This talk will focus on the clinical phenotype of the founder groups and the most recent molecular advances in FA. diagnosis.


DEnTAl AnD CRAnIOFACIAl MAnIFESTATIOnS OF OI III In SA

Manogari Chetty1, Tina Roberts1, lawrence Stephen1, Peter Beighton2

1University of the Western Cape, Cape Town, South Africa, 2University of Cape Town, Cape Town, South Africa

BackgroundOsteogenesis imperfecta type III (OMIM 259420) is a severe autosomal recessive disorder. Affected individuals have multiple fractures, develop limb deformities with spinal malalignment and consequent stunted stature. The frequency of OI III is relatively high in the indigenous Black African population of South Africa. A review of the literature revealed a paucity of information regarding the craniofacial manifestations of the disorder in this ethnic group.

Methods and ObjectivesThe main objective of the study was to identify the dental and craniofacial manifestations in Black African persons in South Africa with Osteogenesis imperfecta type III.

With the support and co-operation of clinical colleagues in Pietermaritzburg, Durban and the Free State, patients with OI III who were under their care, were accessible to the author. This study had predominantly clinical and imaging components in which dental and craniofacial abnormalities in affected persons were documented. A total of 64 Black African affected persons were dentally and craniofacially assessed and the findings were documented.

ResultsPersons with the homozygous and heterozygous mutations did not present with clinically obvious DI in either their primary or permanent teeth. 22 persons with the unknown molecular status had DI in their primary and secondary dentition. These facts are suggestive of molecular heterogeneity in OI III

The craniofacial abnormalities reported are related to the abnormal bone matrix which results in a deformed skull and dental malocclusion. The physiological process of swallowing may be an aetiological factor in the progressive development of a flattened palate. Mild changes in the shape of the head of the mandibular condyle and a lack of cortical bone on the joint surfaces were observed on cone beam computed tomography (CBCT) images. Affected persons had marked variations in the paranasal sinuses, including sinus hypoplasia and partial opacification. Cranial base anomalies were diagnosed from cephalometric radiographs and lateral skull radiographs and Platybasia and a ‘J’ shaped sella turcica were observed.

ConclusionOsteogenesis imperfecta type III is associated with dental and craniofacial abnormalities. These discrepancies impact on dentofacial appearance and masticatory function. A coordinated surgical and clinical approach by a maxillofacial surgeon and an orthodontist is often necessary in order to achieve an optimal aesthetic and functional outcome. The craniofacial abnormalities emphasize the importance of a raised level of awareness in terms of dental management and the challenges.


RARE nEURO-METABOlIC COnDITIOnS CAn nOW BE DIAGnOSED AnD TREATED EARlY WITH InCREASInG AVAIlABIlITY OF GEnETIC TESTInG FOR FOUnDER

MUTATIOnS In BlACK SOUTH AFRICAn FAMIlIES. 3 CASES REPORTS DISCUSSED.

lOUISA BHEnGUNHLS, WITS, JOHANNESBURG,GAUTENG, South Africa

Introduction: Complex metabolic conditions are rare and often missed or late diagnosed due to multi-systemic presentation. Early diagnosis can prevent high mortality rate and long- term complications and appropriate genetic counselling can be offered. 3 Case reports are discussed, one mitochondrial disorder and 2 cases of a lysosomal storage disorder.

Methods: Case 1: A 6 months old black girl presented with postnatal failure to thrive, encephalopathy and 6cm hepatomegaly with highly elevated liver transaminases, hypoglycaemia, hyperlactateamia, highly elevated alpha fetoprotein and ferritin levels. A homozygosity for MPV17 founder mutation confirmed diagnosis of Mitochondrial neuro-hepatopathy syndrome. Mother was counselled for autosomal recessive condition with poor prognosis. Options for future pregnancies were discusssed.

Case 2: A 5 months old black girl presented with muscle wasting and rickets with renal tubular acidosis, hypocalcium and glycosuria and phosphaturia in keeping with Fanconi syndrome. Eye examination showed cystine crystals and elevated cystine in white cells. Diagnosis of Cystenosis was confirmed by detecting compound heterozygosity for founder mutation c971-12 G>A, and c124 G>A mutation, another pathogenic mutation both in the CTNS gene. Early treatment with oral Cysteamine and eye drops was initiated. Parents were offered a full genetic counselling for an autosomal recessive condition.

Case 3: An 18 years old girl presented with photophobia, severe rickets and end- stage renal failure. Also found to have cystine crystals in the eyes and raised cystine in her white cells. Late diagnosis of Cystenosis delayed treatment leading to irreversible kidney failure.

Due to lack of molecular testing, her younger sister was also diagnosed with complications at 3 years of age. Parents were not offered prenatal diagnosis.

Conclusion: With increasing detection founder mutation testing by whole gene sequencing in SA, patients can have better care and offered future carrier testing, prenatal diagnosis and pre-implantation diagnosis.


CHOOSInG THE RIGHT TEST FOR THE RIGHT PATIEnT: FROM PAnElS TO ExOME

Swaroop Aradhaya

Summary:Clinical whole exome sequencing WES) is increasingly being used for diagnosing disorders with broad clinical and genetic heterogeneity. In addition, it is empowering discovery and characterization of novel syndromic pediatric disorders. However, for a number of childhood disorders multi-gene panel sequencing is appropriate and adequate as a first test, and deciding between panels versus WES is a common question in the clinic. On a technical level, clinical-grade WES requires high-quality sequencing and sufficient coverage of all targeted genes. Achieving this quality can be a challenge for any one next-generation sequencing (NGS) workflow and customization is often necessary. In addition, not all NGS methods can produce data on the full spectrum of genetic variants responsible for Mendelian disorders. This seminar will describe the clinical utility of WES, its technical details and limitations, and application in clinical vs research settings.


Whole exome sequencing identifies causative mutations in autosomal recessive nonsyndromic hearing loss patients from Sub-Saharan Africa

Kamogelo lebeko1, Tshepiso Masekoameng1, Jean-Jacques noubiap2, Shaheen Mowla3, Collet Dandara1, Guillaume Paré4, Richard Smith5, Ambroise Wonkam1

1Division of Human Genetics, Faculty of Health Sciences,University of Cape Town, Cape Town, South Africa, 2Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa, 3Division of Heamatology, Faculty of

Health Sciences, University of Cape Town, Cape Town, South Africa, 4Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, Ontario, Canada, 5Department of Otolaryngology, University of Iowa, Iowa City, USA

Introduction: Hearing loss is the most common communication disorder affecting about 6/1000 births in developing countries. Up to 50% is attributed to genetic factors with nonsyndromic hearing loss being the most common form of hearing loss. The common genetic factors contributing to autosomal recessive nonsyndromic hearing loss (ARNSHL) amongst African patients are yet to be elucidated. Previously, we employed targeted exome sequencing (TGE) using OtoSCOPE to uncover causative mutations harboured by this underrepresented population group. We identified 12 causative mutations from 7 families presenting with ARNSHL. In this present study, we aimed to compare the efficacy of whole exome sequencing (WES) to that of TGE through OtoSCOPE in identifying mutations in known hearing loss genes as well as to be able to uncover mutations in new hearing loss genes. Four families from Cameroon previously subjected to the OtoSCOPE panel were selected for WES and results were compared to those reported through OtoSCOPE. Novel mutations identified in previously unresolved families were interrogated using bioinformatic analysis and a cell line model was used to observe the effect of the mutations in vitro. Molecular analysis of novel mutations was performed using direct Sanger sequencing on 80 patients and 100 matched controls. Three of the four (3/4) families were resolved using WES, including a previously unresolved family. A novel frameshift mutation, c.251_delC, was identified in GRXCR2 for Family 8. PSIPRED analysis shows that this protein is mostly disordered and carries a zinc finger motif at the C-terminus end. We have identified this mutation in another patient in our cohort and functional studies are still ongoing. This study demonstrates that WES is the best approach to use when investigating ARNSHL as it is able to identify mutations which would be detected by targeted exome sequencing as well as new mutations in new genes which TGE panels would not detect. It is also the first to use WES in resolving ARNSHL amongst African patients. GRXCR2 has rarely been reported in association with HL, and this present study is the second to report on its role. An unresolved family shows that there are other genetic causes of ARNSHL outside of the exome which need to be investigated. The use of whole genome sequencing and detection of copy number variations is suggested.


A BIOInFORMATICS AnAlYSIS OF THE GEnETICS OF HEARInG IMPAIRMEnT In A CAMEROOnIAn POPUlATIOn USInG WHOlE ExOME SEQUEnCInG.

noluthando Manyisa, Emile Chimusa, Collet Dandara, Ambroise WonkamUniversity of Cape Town, Cape Town, South Africa

Hearing impairment (HI) is the inability to detect sound lower than 25Db and it is considered disabling when an individual cannot detect sound lower than 30dB. Disabling hearing impairment has the highest prevalence in developing countries, such as Cameroon, which have an estimated prevalence of 6/1000 live births. Mutations in GJB2 and GJB6, which are responsible for most cases of autosomal recessive non-syndromic hearing impairment (ARNSHI), have been shown to be insignificant among African populations. To resolve ARNSHI in the Cameroonian population, we have employed whole exome sequencing (WES) amongst an unaffected control and HI patient population, to discover variations that may be prevalent within the population. The aim of this project is to use WES to assess the frequency of pathogenic variants in known and potentially novel HI genes among unaffected control and HI populations from Cameroon. 118 unaffected control participants and 18 HI participants, who were negative for mutations in GJB2, GJB6, and GJA1, were selected for the present study. The participants underwent WES and the data was analysed using custom python, bash, and R scripts and publicly available databases. The data was then analysed for genetic differentiations between the control and the HI cohorts and the proportion of derived and ancestral alleles were determined, where the ancestral alleles are conserved alleles within species and the derived alleles are associated with disease risk. Variations in FOXD4L6, DHRS4L2, RPL3L, and VTN are significantly associated with the HI cohort, with RPL3L and VTN interacting with known HI associated genes. In performing a community network analysis, VTN is shown to be a hub protein in a network that includes three HI associated genes. VTN, among other genes, is significantly genetically different between the control and HI cohorts. The HI cohort has also been shown to have, an increased proportion of derived alleles at low minor allele frequencies.


ExPlORATIOn OF THE GEnETIC VARIAnTS ASSOCIATED WITH TYPE 2 DIABETES USInG nOVEl WHOlE-GEnOME SEQUEnCES In InDIVIDUAlS OF SETSWAnA

DESCEnT In SOUTH AFRICA

Tinashe ChikoworeUniversity of Witwatersrand, Johannesburg, South Africa

The burden of Type 2 diabetes is a major global public health concern. In Africa, where it is estimated that T2D prevalence will have the highest increase by 2030, more efforts are now required to curb this burden. In view of the strong heritability of T2D, unravelling the underlying genetic factors might help in the development of effective and personalised interventions to limit this disease. The genetic determinants of T2D, however, have not been explored using whole-genome sequences that can enable the detection of rare variants which are postulated to have large effects on T2D risk in Africa. We therefore evaluated the genetic variants associated with T2D among 16 T2D cases and 14 controls that were selected from the extremes of the glycated hemoglobin distribution. Single variant and gene-based tests were performed with the EPACTS pipeline software while adjusting for age, sex, and BMI and population structure using EMMAX linear mixed modelling. The rs7499753 SNP, located in the intron of CIITA, attained association with T2D risk beyond the genome-wide significance level at p = 1.45 x 10-8. Some coding SNPs with nominal significance (p < 5 x 10-5), which will need to be validated in future studies, were discovered. Through collaborative efforts, we noted for the first time that the Setswana, Zulu and Sotho ethno-linguistic groups shared a common ancestry and might be closely related. However, well-powered collaborative whole genome sequencing initiatives are required to elucidate the genetic variants associated with T2D among black South Africans.


ExOME SEQUEnCInG IDEnTIFIES A nOVEl TTC37 MUTATIOn In THE FIRST REPORTED CASE OF TRICHOHEPATOEnTERIC SYnDROME (THE-S) In SOUTH AFRICA.

Craig Kinnear1, Brigitte Glanzmann1, Erica Banda1, nikola Schlechter1, Glenda Durrheim1, Annika neethling1, Etienne nel3, Mardelle Schoeman1, Glynis Johnson1, Paul van Helden1, Eileen Hoal1, Monika Esser2, Michael Urban1, Marlo

Moller1

1SAMRC Centre for Tuberculosis Research, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, St, Cape Town, South Africa, 2National Health Laboratory Service, Immunology Unit, Division of Medical Microbiology, Department of Pathology, Tygerberg Hospital,

Stellenbosch University., Cape Town, South Africa, 33Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa

Background: Trichohepatoenteric syndrome (THE-S) or phenotypic diarrhoea of infancy is a rare autosomal recessive disorder characterised by severe infantile diarrhoea, facial dysmorphism, immunodeficiency and woolly hair. It was first described in 1982 in two infants with intractable diarrhoea, liver cirrhosis and abnormal hair structure on microscopy. We report on two siblings from a consanguineous family of Somali descent who, despite extensive clinical investigation, remained undiagnosed until their demise. The index patient died of fulminant cytomegalovirus pneumonitis at 3 months of age.

Methods: Whole exome sequencing (WES) was performed on a premortem DNA sample from the index case. Variants in a homozygous recessive state or compound heterozygous state were prioritized as potential candidate variants using TAPERTM. Sanger sequencing was done to genotype the parents, unaffected sibling and a deceased sibling for the variant of interest.

Results: Exome sequencing identified a novel homozygous mutation (c.4507C>T, rs200067423) in TTC37 which was confirmed by Sanger sequencing in the index case. The identification of this mutation led to the diagnosis of THE-S in the proband and the same homozygous variant was confirmed in a male sibling who died 4 years earlier with severe chronic diarrhoea of infancy. The unaffected parents and sister were heterozygous for the identified variant.

Conclusions: WES permitted definitive genetic diagnosis despite an atypical presentation in the index case and suggests that severe infection, likely secondary to immunodeficiency, may be a presenting feature. In addition definitive molecular diagnosis allows for genetic counseling and future prenatal diagnosis, and demonstrates the value of WES for post-mortem diagnosis of disorders with a non-specific clinical presentation in which a Mendelian cause is suspected.


ExOME SEQUEnCInG OF THE FIRST REPORTED SOUTH AFRICAn x-lInKED PRIMARY IMMUnODEFICIEnCY CASE IDEnTIFIES A HEMIZYGOUS MUTATIOn In MSN

Brigitte Glanzmann1, Marlo Möller1, Eileen Hoal1, Mardelle Schoeman1, Paul van Helden1, Michael Urban1, Monika Esser2, Craig Kinnear3

1Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa, 2National Health Laboratory Service, Immunology Unit, Tygerberg, Division Medical Microbiology, Department of Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa, 3SA MRC Centre for Tuberculosis Research, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Division of

Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, S, Cape Town, South Africa

Primary immunodeficiency diseases (PIDs) are a subgroup of immunological disorders that are inherited and which increase susceptibility to viral infections. Single-gene defects may lead to disease manifestations that range from extremely narrow infectious phenotypes to broad multisystem defects. Here, we present the findings of a patient who presented with non-resolving lymphopenia and neutropenia following a bout of pneumonia.

Whole exome sequencing was performed and the data was processed using and in-house bioinformatics pipeline, TAPER™. Candidate variants were subsequently validated using Sanger sequencing.

A hemizygous missense mutation (c.511C>T; p. R171W) in exon 5 of MSN was identified. Sanger sequencing subsequently revealed that the variant was heterozygous in the mother and absent from the father of the index case. Moreover, the same mutation was identified in the maternal uncle of the index case who is also affected.

The R171W mutation identified in MSN has previously been associated with PID, but this is the first known reported case in South Africa and only the eighth patient worldwide. Our findings not only emphasise the importance of an accurate molecular diagnosis, but also allow for improved patient management and treatment. Moreover, the use of WES is a cost-effective and accurate means of molecular diagnosis in resource constrained countries such as South Africa.


Tuesday 15 August 2017

SEx-SPECIFIC InBREEDInG DEPRESSIOn In HUMAnS

Jim Wilson

Inbreeding depression - reduced evolutionary fitness in the offspring of related parents - is observed in many plant and animal species, and is thought to have played an important role in the evolution of outcrossing mating systems. Here, in a analysis of over one million individuals, we show that increased autozygosity, caused by parental relatedness, has a statistically significant effect on 11 of 42 human complex traits analysed. For the first time in a genetic study, we show that increased autozygosity reduces reproductive success in humans, as well as influencing medically important traits associated with survival and reproduction. In addition, we observe that, for many traits, the effect of inbreeding is significantly greater in men than in women, consistent with observations in other species where the more heavily selected sex suffers greater inbreeding depression. We present evidence that the observed effects are caused by genetic factors and not by unobserved environmental confounders. In particular, the effect of autozygosity is consistent across diverse populations, and a linear relationship is observed between autozygosity and phenotypic changes. The other things you requested are below.


GEnETIC SCREEnInG In BlACK SOUTH AFRICAn PARKInSOn’S DISEASE PATIEnTS FOR PATHOGEnIC MUTATIOnS USInG A TARGETED RESEQUEnCInG APPROACH

Oluwafemi Oluwole1, Shameemah Abrahams1, Jonathan Carr2, Helena Kuivaniemi1,3, Soraya Bardien1

1Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg Campus Cape Town, South Africa, 2Division of Neurology, Faculty of Medicine and

Health Sciences, Stellenbosch University, Tygerberg Campus Cape Town, South Africa, 3Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg Campus Cape Town, South Africa

Background: Parkinson’s disease (PD) is a neurodegenerative disease that affects over seven million people worldwide, and is one of the leading contributors to disabilities globally. PD-causing mutations in a number of genes have been identified and studied in various European, North-American and Asian countries but little is known about the genetics of PD in sub-Saharan Africa (SSA) and Information from other populations may not be applicable in SSA. A pilot study by our group investigated the performance of a targeted next-generation sequencing approach (tNGS) to screen for pathogenic mutations in seven South African PD patients including three black, three white-Afrikaners and one mixed ancestry individuals, the study showed that this technique is effective, and black individuals appeared to have more single nucleotide variations (SNVs) and indel. The goal of the present study was to screen for mutations in candidate genes in 34 black South African PD patients using tNGS.

Methods: Genomic DNA was extracted from blood samples of 34 black South African PD patients. The DNA quality was assessed using gel electrophoresis and on an Agilent Bioanalyzer 2100. Barcoded and non-barcoded sequencing libraries containing DNA fragments (200 to 300bps) flanked by the Ion AmpliSeq™ Neurological Research Panel (Thermo Fisher Scientific) adapters comprising 751 genes were produced, and sequencing was done on an Ion-Torrent PGM. Ion Reporter software 5.2 was used for the data analysis.

Results: All 34 DNA samples produced good quality sequencing reads. A total of 125,012 variants were identified, with an average of 3,677 variants per sample in the 751 genes analyzed. A total of 794 exonic and 2,028 intronic variants were found in the 15 known PD genes. These included 55 splice site, 7 frameshift and 340 missense variants. A total of 311 rare variants (MAF<0.01) identified are in dbSNP. Of these, 82 were not identified in the PDGene database cataloguing only PD-associated variants. We identified 19 novel potentially pathogenic variants in two autosomal dominant and six autosomal recessive PD genes.

Conclusion: A large number of putative pathogenic variants were identified, in silico pathogenic analysis of these SNVs suggested that they may be pathogenic, but their functional significance in PD needs to be elucidated in further studies. The novel variants in PD genes identified in the South African black patients is an indication to further study this population for possible genetic causes of PD.


A nOVEl InTERACTIOn IDEnTIFIED BETWEEn lRRK2 AnD THE TOM PROTEIn COMPlEx WHICH PROVIDES POSSIBlE ClUES TO THE AETIOlOGY OF PARKInSOn’S

DISEASE

Annika neethling1, Lize Engelbrecht3, Ben loos3, Monique Williams1,2, Soraya Bardien1

1Stellenbosch University, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, South Africa, 2Stellenbosch University, DST/NRF Centre of Excellence in Biomedical Tuberculosis Research, SA MRC Centre for Tuberculosis

Research, South Africa, 3Stellenbosch University, Department of Physiological Sciences, Faculty of Science, South Africa

IntroductionParkinson’s disease (PD) is a progressive, complex and incurable neurodegenerative disorder in which mitochondrial dysfunction is thought to play an important role. Although the exact aetiology remains unclear, several mutations in LRRK2 have been implicated in the development of autosomal dominant PD. Also, recently, the translocase of outer mitochondrial membrane (TOM) complex, which plays a role in the maintenance of healthy mitochondria, has been implicated in PD pathogenesis.

The aim of this study was to identify additional pathways in which LRRK2 function through investigating the possible association between LRRK2 (wild type and mutant) and the TOM complex under basal [Dimethyl sulfoxide (DMSO)] and stress-induced [Carbonyl cyanide m-chlorophenyl hydrazone (CCCP, a mitochondrial uncoupler)] conditions.

MethodsCo-localization experiments of LRRK2 and the TOM complex was performed using super resolution structured illumination microscopy (SR-SIM), while protein-protein interactions were investigated using co-immunoprecipitation and Western blot analysis in an overexpression model of LRRK2.

ResultsWild type (WT) LRRK2 was shown to associate with the TOM complex under basal and stress conditions. Studies are ongoing to investigate the effect of mutant LRRK2 (G2019S, I2020T and the novel variant, Q2089R) on this association. We are expecting to observe altered association with mutant LRRK2 and the subunits of the TOM complex.

ConclusionIn conclusion, we identified novel interacting partners of LRRK2 and propose a model for LRRK2’s involvement in cellular functioning and cell death. Future targeted experiments on LRRK2 are however needed to unravel the complex pathobiology and to decipher the sequence of events that lead to development of PD in susceptible individuals.


WHOlE ExOME SEQUEnCInG FOR MUTATIOn DISCOVERY In SOUTH AFRICAn PEDIGREES WITH PARKInSOn'S DISEASE

Kamogelo lebeko


THE USE OF WHOlE ExOME SEQUEnCInG TO InVESTIGATE THE AETIOlOGY OF FAMIlIAl PARKInSOn’S DISEASE In A SOUTH AFRICAn AFRIKAnER FAMIlY

Boiketlo SebateStellenbosch University, Cape Town, South Africa

Background: The development of high-throughput next generation sequencing (NGS) technologies has fast-tracked the discovery of disease-causing genetic variants, making it both technically and financially feasible as a means of studying Mendelian disorders such as familial forms of Parkinson’s disease (PD). PD is a neurodegenerative disorder with varied clinical features including tremor, muscular rigidity and postural instability. The aim of this study is to utilize whole exome sequencing (WES) to identify novel pathogenic candidate mutations in a South African Afrikaner family with an autosomal dominant form of PD. Methods: WES data were generated on the Ion Proton™ System from three affected and three unaffected family members. FASTQC, Novoalign, Samtools and ANNOVAR were employed for quality control and annotation purposes before a stringent prioritization and filtration process was applied to the data. Results: Using bioinformatics analysis and a comprehensive filtration method to prioritise the variants, we identified seven non-synonymous co-segregating variants predicted to be potentially disease-causing. Three candidate variants had the highest scores in terms of deleteriousness across all five prediction tools SIFT, PolyPhen-2, MutationTaster2, CADD, and GERP++. The three candidate genes are NRXN2 (a presynaptic transmembrane protein), POU2F1 (a ubiquitous transcription factor) both of which are members in pathways related to the known PD gene SNCA. As well as CDC27 (a subunit of an E3 ubiquitin ligase complex) which interacts with known PD genes UCLH1 and SNCA. Further work such as Sanger sequencing, for the verification of variants, and screening of ethnically-matched controls to assess the variant frequency in the population, are ongoing. Future work will involve functional studies to determine the effect of the variant in an appropriate cellular disease model. Conclusions: To date, research from our group has established that the known PD genes are a minor contributor to disease susceptibility in the genetically unique South African population. This suggests the possibility of discovering novel PD-causing genes in South African patients. However, the challenge of analysing WES data remains in applying the appropriate variant filtering strategies to effectively prioritise the variants into a workable list of candidates without ‘throwing the baby out with the bathwater’.


THE PATHWAY TO ElUCIDATInG BIPOlAR DISORDER GEnETICS

Hannah-Ruth Engelbrecht1, Shareefa Dalvie1,2, Dan J Stein2, Rajkumar S Ramesar1

1Division of Human Genetics, University of Cape Town, Cape Town, Western Cape, South Africa, 2Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, Western Cape, South Africa

Introduction: Bipolar disorder (BD) is both a clinically and genetically complex disease with a global prevalence of approximately 1%. However, despite high heritability rates of 85%, there is no consensus with regards to the genetic origins of the disease which has serious effects on the lives of those who must live with it. Extended family studies of BD limit the heterogeneity in the data, but recent studies have focussed on large case-control models. The aim of this study is to use whole -genome sequencing data and a bioinformatics approach to identify genetic variants for BD in an affected Afrikaans family, and identify potential pathways that may have a role in this debilitating disorder, which will be extrapolated to a cohort of families afflicted with BD to determine the common origins of this disorder.

Methodology: Whole genome sequences of 4 BD-affected family members were used for KEGG pathway-based pathway analysis, as a means of observing what biological processes may underlie the disorder. Several platforms, KOBAS 3.0, DAVID, and WebGestalt, were used. Candidate variants were selected following prioritisation methods and comparisons to previously-associated genes from association studies. These candidate variants will be genotyped using TaqmanTM technology, and will be used in an extended family-based association test (FBAT) in a cohort of approximately 500 individuals.

Results: Principal components analysis illustrated that the Dutch genome was an appropriate control for the Afrikaans genome in the absence of WGS data from an unaffected Afrikaans family member. Pathway analysis indicated the influence of pathways in cancer (HSA05200), regulation of the actin cytoskeleton (HSA04810), and focal adhesion (HSA04510) in the Afrikaans BD-affected family members.

Discussion/Conclusion: The pathways discovered in this study have been implicated previously in this disorder, and give some insight into the nature of BD as an illness. The data confirm that basal cellular functions could be involved in the pathophysiology of BD, and indicate that further investigation into the cellular regulatory mechanisms involved in BD manifestation should be investigated using next-generation methods.


EHlERS DAnlOS SYnDROME - A nATIOnAl DIAGnOSTIC SERVICE

Glenda Sobey

The term Ehlers-Danlos Syndrome (EDS) refers to a group of inherited connective tissue disorders. In many subtypes the genetic basis is now known. The skin, joints, blood vessels and hollow organs can all be affected with consequences varying from mild features to severe life threatening events. The accurate diagnosis of EDS, can allow specific management, family screening and prenatal diagnosis.

The development of the EDS National Diagnostic Service serves as a paradigm for service development to meet the needs of patients with rare disesase.


CHROMOSOMAl MICROARRAY AS A FIRST lInE DIAGnOSTIC TEST In PATIEnTS WITH COnGEnITAl ABnORMAlITIES/DEVElOPMEnTAl DElAY In SOUTH AFRICA

lindsay lambie1, Zane lombard1, Brynn levy2, Amanda Krause1

1Division of Human Genetics, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand; National Health Laboratory Service, Johannesburg, South Africa, 2Department of Pathology and Cell Biology, Columbia University, College of

Physicians and Surgeons, New York, USA

Background and aim: Unexplained developmental delay (DD), multiple congenital abnormalities (MCA) and autism spectrum disorder (ASD) are common indications for genetic investigation. Conventional karyotyping detects chromosomal abnormalities in only 3% of these patients (excluding common trisomies). Chromosomal microarray (CMA) increases this detection rate to 15-20%, hence its use as a first-line diagnostic test. CMA has not been available locally, and in our resource limited setting, we have used a lower resolution technique, Multiplex Ligation-dependent Probe Amplification (MLPA), as an additional test to detect submicroscopic chromosome abnormalities. We evaluated the potential of using CMA as a first line diagnostic test in our setting and provide a preliminary cost analysis to evaluate the feasibility of this.

Methodology: A total of 48 patients, with DD, MCA and/or dysmorphic features were selected, in whom CMA was indicated to either clarify/confirm a prior result or in whom available diagnostic testing was negative. All these patients had been assessed clinically in the Division of Human Genetics. CMA (Affymetrix, Cytoscan® Optima) was performed on existing DNA samples from these patients, who had given prior consent for further testing. The outcomes of prior testing were categorized as correct, incomplete, indeterminate or negative, and the average cost per patient of these investigations was compared to the cost of using CMA as a first-line investigation.

Results: Of the 48 patients selected, one was excluded due to a poor quality DNA (n=47). Eighteen (38%) patients had an abnormal result on prior testing, of which 15 (32%) represented a correct diagnosis. 30% of prior results were either incomplete or indeterminate, of which all were resolved by CMA, and the remainder were negative on prior testing and CMA. The average cost of current testing, per patient with an abnormal result, exceeds the cost of performing a first line CMA by 20%, whilst in patients with a negative result, the cost of karyotype and MLPA, vs CMA, is similar. Cases for which CMA provided significant diagnostic advantage are highlighted.

Conclusion: CMA provides comprehensive chromosomal information in a single cost-effective test, and should be considered as a first-line investigation in South Africa.


DElInEATIOn OF THE GEnETIC CAUSES OF EPIlEPTIC EnCEPHAlOPATHY In SOUTH AFRICAn PAEDIATRIC PATIEnTS.

Alina Esterhuizen1,2, Heather Mefford1,5, Raj Ramesar1,2, Gemma Carvill4, Jo Wilmshurst3

1NHLS, Cape Town/Western Cape, South Africa, 2Division of Human Genetics, University of Cape Town, Cape Town/Western Cape, South Africa, 3Paediatric Neurology, Red Cross War Memorial Children’s Hospital, Cape Town/Western Cape, South

Africa, 4Department of Neurology, Northwestern University, Chicago, USA, 5Department of Pediatrics, University of Washington, Seattle, USA

PURPOSE: Sub-Saharan Africa bears the highest burden of epilepsy in the world as a consequence of high incidence of CNS infections, perinatal insults and traumatic brain injury. Genetic epilepsy is underdiagnosed due to lack of awareness and unavailability of genetic testing for epilepsy. In this study we aim to describe the genetic architecture of severe infantile seizure disorders in South African patients and establish a framework for genetic testing in South Africa and Africa more broadly.

METHODS: We recruited 92 South African children diagnosed with epileptic encephalopathy (EE), on the basis of clinical semiology and neurophysiological studies: 46 Indigenous Black, 35 Mixed Ancestry and 11 Caucasian South African children. Of these, 21 were clinically suspected to have Dravet Syndrome (DS). Targeted resequencing of 71 known EE genes and chromosomal microarrays were deemed appropriate, was performed. Patient recruitment is ongoing and we aim to recruit and test 200 patients.

RESUlTS: Pathogenic de novo mutations were identified in 35 patients. SCN1A mutations were found in 9/21 (43%) of the Dravet group, which was markedly less than the published frequency of SCN1A mutations in DS. Clinical reassessment with the screening test by Hattori et al., (2008) resulted in a changed working diagnosis of 5 SCN1A-negative patients in the Dravet group. SCN1A variants were also found in 2 patients of the remaining cohort, who are undergoing clinical reassessment emphasising the value of a genetic diagnosis. In the larger cohort, likely pathogenic changes were detected in 18 genes. A 16p13.11 deletion was detected in 1 patient, additional microarray analysis is ongoing.

COnClUSIOn: These results carry implication for patient management and present valuable insights into disease presentation, motivating translation into diagnostic practice even in the resource-limited African setting. This is the first genetic research study of epilepsy in South African patients.


THE WnT PATHWAY In SYSTEMIC SClEROSIS

Jacqueline Frost1, Michele Ramsay2,1, xavier Estivill3, Mohammed Tikly1

1University of the Witwatersrand, Johannesburg, South Africa, 2Sydney Brenner Institute for Molecular Biosciences, Johannesburg, South Africa, 3Center for Genomic Regulation (CRG), Barcelona, Spain

Systemic sclerosis (SSc) is a complex autoimmune disease involving the immune system, vasculature and extracellular matrix. Dysregulation of the Wnt pathway has been implicated in the development of fibrosis in SSc and is proposed to contribute to a failure to maintain tissue homeostasis and appropriate immune response. The objective of this study was to explore the role of altered Wnt pathway gene regulation in the development of fibrosis in black South African SSc patients with early, diffuse disease (dcSSc). The first aim was to examine differential gene expression in the Wnt pathway and the second aim to examine differential expression of microRNAs that potentially target Wnt pathway genes. Skin biopsies from eight black South African patients with dcSSc, samples from both affected and unaffected skin, and eight ethnically matched healthy control skin samples were examined. The Wnt pathway Profiler qPCR Array (84 Wnt pathway genes) was used to assess differential gene expression, and small RNA-sequencing for microRNA analysis. Data analysis was done using HTqPCR, NormqPCR and DESeq2 software. Gene expression patterns revealed five distinct differentially expressed gene clusters. Two clusters displayed genes that were upregulated in both affected and unaffected SSc skin compared to controls (one showing a more heterogeneous pattern than the other). Another showed consistently decreased gene expression and two revealed more complex patterns responsible for delineating the patients into two groups. The gene expression was validated for five genes. The sRNA-seq data showed differential expression of 31 miRNAs that target the Wnt pathway genes, including miR-335 and miR204 that are important regulators of normal tissue development. Other dysregulated miRNAs have been linked to fibrotic and autoimmune diseases. In this group of dcSSc patients, there is differential gene expression of several Wnt pathway genes that delineate the patients into two distinct groups. This could point to differences in disease aetiology leading to distinct clinical outcomes, such as inflammation. Together with the differentially expressed microRNAs, the findings indicate a substantial contribution of epigenetic changes to the pathogenesis, progression and diverse clinical features of dcSSc.


HIGH InCIDEnCE, ClInICAl PRESEnTATIOn AnD PROPOSED DISEASE MECHAnISM OF MITOCHOnDRIAl nEUROHEPATOPATHY In 22 BlACK SOUTH AFRICAn InFAnTS

HOMOZYGOUS FOR A nOVEl PATHOGEnIC VARIAnT In THE MPV17 GEnE.

Surita Meldau1,2, Ronalda Delacey1,3, Gillian Riordan1,3, Elizabeth Goddard1,3, Komala Pillay1,2, Karen Fieggen1,4, David Marais1,2, George Van der Watt1,2

1University of Cape Town, Cape Town, Western Cape, South Africa, 2National Health Laboratory Services, Cape Town, Western Cape, South Africa, 3Red Cross War Memorial Childrens Hospital, Cape Town, Western Cape, South Africa, 4Grootte Schuur

Hospital, Cape Town, Western Cape, South Africa

OBJECTIVES: To describe the clinical and laboratory findings in 22 Black South African infants with mitochondrial neurohepatopathy due to a novel founder mutation in the MPV17 gene.

METHODS: Following identification through exome sequencing of a novel MPV17 pathogenic variant in two patients with early onset mitochondrial neurohepatopathy, and demonstration of a high carrier frequency (1/68) and predicted population disease incidence (1/18 496), a cost effective RFLP test was introduced at the NHLS IMD laboratory. All subsequent suspected cases referred to our unit were screened for the same variant after review of presenting clinical information. cDNA analysis was performed on mRNA extracted from skin fibroblasts of two affected patients to establish the functional effect of this variant at an mRNA and protein level.

RESUlTS: To date, 22 black South African patients have been diagnosed with mitochondrial neurohepatopathy. All were homozygous for the c.106C>T mutation in MPV17. Main clinical and laboratory features include conjugated hyperbilirubinaemia, hypotonia, global motor delay, lactataemia, moderate transaminitis, hypoalbuminaemia, hypoglycaemia (in some) and coagulopathy. Histological findings included microvesicular steatosis, oncocytes and cholestasis with enlarged, crowded mitochondria on electron microscopy. cDNA analysis revealed replacement of the normal MPV17 transcript in patient fibroblasts by a shortened mRNA transcript (lacking exon 3) in patient but not control cell lines.

COnClUSIOnS: Mitochondrial neurohepatopathy due to the c.106C>T mutation in the MPV17 gene should be considered as a differential in Black South African babies presenting with early onset liver disease, hypotonia and global motor delay.


GEnETIC AnAlYSIS OF InHERITED RETInAl DISEASES In InDIGEnOUS SOUTHERn AFRICAn POPUlATIOnS

lisa Roberts1, Anand Swaroop2, Raj Ramesar1

1UCT/MRC Human Genetics Research Unit, Division of Human Genetics, Department of Pathology, Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape, Cape Town, Western Cape, South

Africa, 2Neurobiology, Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA

Inherited retinal diseases (IRDs) are a group of clinically and genetically heterogeneous disorders which cause degeneration of photoreceptor cells in the retina, resulting in visual impairment. Investigations into IRDs have been ongoing in South Africa for more than 30 years, however, the evaluation of reported genetic mutations has yielded low returns, particularly in indigenous Southern Africans, indicating a mutation spectrum which is dissimilar to that elsewhere. Indigenous Africans comprise a unique population group with distinct genetic diversity, thus providing a valuable resource for genetic discoveries, yet they remain largely underrepresented in genomic studies. The aim of this investigation was to characterise the underlying genetic mutations in a cohort of indigenous African IRD patients. As part of this study, the IRD registry at the Division of Human Genetics (University of Cape Town) was reviewed, leading to the characterisation of a founder mutation causing Usher syndrome in this population group. In addition, next generation sequencing (NGS) technology, namely whole exome sequencing (WES), was performed on individuals from 16 families, which had remained undiagnosed after screening for known mutations using genotyping-based microarrays. The WES analysis revealed a novel IRD gene in one family, and mutations in known IRD genes which were causative of disease in 10 families. Furthermore, the identification of mutations in known X-linked genes highlighted key considerations for IRD WES analysis. Importantly ~70% of the mutations identified through WES were novel, emphasising the superiority of NGS-based approaches compared to microarrays which screen for IRD mutations reported in other (mainly European-derived) populations. Cascade screening of mutations identified in this study, across larger cohorts of unrelated probands, resulted in the genetic diagnosis of additional families. Therefore, as a result of this investigation, the number of indigenous African families in the IRD registry with a genetic diagnosis was effectively doubled. Members of these families can now opt for diagnostic, carrier, or predictive testing of familial mutations. Finally, the information gathered from this research contributes towards a better understanding of IRDs in South Africa.


IDEnTIFICATIOn OF nOVEl CAnDIDATE GEnES FOR SUSCEPTIBIlITY TO TUBERCUlOSIS BY IDEnTIFYInG DISEASE-CAUSInG MUTATIOnS In InDIVIDUAlS

WITH PIDS

nikola Schlechter1, Brigitte Glanzmann1, Eileen Hoal1, Mardelle Schoeman3, Britt-Sabina Petersen2, Andre Franke2, Michael Urban3, Paul van Helden1, Marlo Moller1, Monika Esser4, Craig Kinnear1

1SA MRC Centre for TB Research, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosc, Western Cape, South Africa, 2Institute

of Clinical Molecular Biology, Kiel University, Kiel, Germany, 3Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Western Cape, South Africa, 4Immunology Unit National Health

Laboratory Service Tygerberg, Division Medical Microbiology, Department of Pathology, Stellenbosch University, Western cape, South Africa

Although approximately 33% of the world’s population is infected with M.tuberculosis, the causative agent of tuberculosis (TB), only 10% of infected individuals will develop active disease. While the genotype of invading strain and environmental factors are crucial in disease outcome, host genetic factors can be decisive. Several investigations have successfully identified genes involved in TB susceptibility. Nevertheless, it is certain that more susceptibility genes exist, but identifying them in a complex disease such as TB is challenging. Answers may lie in the genomes of individuals suffering from a group of inherited primary immunodeficiency disorders (PIDs) for which multiple M.tuberculosis infections is a common feature. We hypothesize that the genes involved in these PIDs could be candidate genes for increased TB susceptibility in the general population. We aimed to identify novel TB susceptibility genes by finding gene mutations in patients suffering from PIDs characterized by increased TB susceptibility.

The exomes of three PID patients and five of their healthy parents were sequenced using the Illumina HiSeq. Bioinformatic techniques were used to identify a large number of variations from the reference human genome for each patient. The genes were prioritized based on OMIM and HGMD database entries to result in the identification of three novel putative disease-causing variants, one per patient, situated in two novel susceptibility genes namely MAP3K14 and TAP1. All three variants were absent from ethnically matched controls, and were predicted to be deleterious and disease-causing by most in silico prediction tools used. Overexpression models were used to functionally prove that the variant identified in MAP3K14 decreases the kinase activity of this protein, and thus result in significantly decreased nuclear factor-kappa B (NF-κB) signalling.

The identification of these disease-causing mutations can provide us with novel candidate genes to screen for TB susceptibility in the general population.


DESIGnInG THE H3AFRICA GEnOTYPInG ARRAY

Ananyo Choudhury1, Gerrit Botha2, Emile Chimusa2, Mamana Mbiyavanga2, Ayton Meintjes2, Adebowale Adeyemo3, Zane lombard1, Scott Hazelhurst1, nicola Mulder2

1University of the Witwatersrand, Johannesburg, Gauteng, South Africa, 2University of Cape Town, Cape Town, Western Cape, South Africa, 3National Institutes of Health, Bethesda, MD, USA

Despite a significant decrease in the cost of whole genome sequencing (WGS) in the recent years, single nucleotide variant (SNV) genotyping arrays remain the stalwart of genetic association studies. They are cost effective and it is easy to store and analyse the data. The arrays currently used for population-genetic and genome-wide association studies (GWAS) in African populations predominantly represent common Eurasian genetic variation and have limited power in capturing the enormous genetic diversity in Africans. Moreover, intrinsic differences in LD architecture between African and non-African populations restrict their ability to identify association signals in Africans.

The aim was to design a 2.5 million SNP array for the Human Health and Heredity in Africa (H3Africa) Consortium as an Africa-centric, unbiased, cost-efficient solution for genomic research on the continent. An unprecedented dataset of over 2500 unpublished African whole genomes and novel algorithms was used to design the array ensuring considerably better representation of African LD architecture, thereby increasing the chance of detecting association signals and narrowing down the positions of causal variants. The array in addition includes thousands of novel common African variants and has a comprehensive coverage of variants of potential clinical and pharmacogenomics significance from the GWAS-Catalog, ClinVar, Cosmic and PharmGKB databases.

Computational comparative analyses showed that the H3Africa array significantly outperforms currently available arrays of similar size in terms of genomic coverage and imputation accuracy in African populations. The H3Africa array will provide a tool for researchers to discover novel disease associations in an African setting, and is commercially available through Illumina.


KERATOlYTIC WInTER ERYTHEMA: FROM CHROMOSOMAl lOCAlISATIOn TO CAUSAl MUTATIOn In 20 YEARS

Thandiswa ngcungcu


TRAnSFORMInG THE WAY CYSTIC FIBROSIS IS DIAGnOSED

Cheryl Stewart1,2, Jeanne van Rensburg1,2, Ovokeraye Oduaran1,2, Marco Zampoli3,4, Tamara Kerbelker3,4, Refiloe Masekela1,5, Ashley Jeevarathnum1,5, Robin Green1,5, Debbie White6,7, Shelley Macaulay7, Catherine Baird6,7, Michael

Pepper1,2

1University of Pretoria, Pretoria, South Africa, 2Institute for Cellular & Molecular Medicine, Pretoria, South Africa, 3Red Cross War Memorial Children’s Hospital, Cape Town, South Africa, 4University of Cape Town, Cape Town, South Africa, 5Steve Biko Academic Hospital, Pretoria, South Africa, 6Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa,

7University of the Witwatersrand, Johannesburg, South Africa

Cystic fibrosis (CF) is caused by mutations in the CFTR gene and follows an autosomal recessive inheritance pattern. CF is a life-shortening illness with South African patients having a life expectancy of 20.5 years. CF patients tend to have chronic chest infections and fail to thrive. The annual maximum treatment cost per CF patient is approximately R360,000. CF is caused by population-specific mutations that vary by race and country. The genetic tests for CF all have an inherent bias toward European populations, increasing the likelihood that non-European CF patients will receive a false negative test result. This can delay diagnosis or result in misdiagnosis which is linked to a significantly worse prognosis for CF patients.

In order to identify mutations that are relevant to South African populations, suspected CF patients at the Steve Biko Academic, Charlotte Maxeke Johannesburg Academic, and Red Cross War Memorial Children’s Hospitals were recruited. DNA was extracted from the venous blood of 57 patients which was subjected to next generation sequencing (NGS). This cohort was racially diverse and had 27 patients with an unknown genotype and 30 who had had only one mutation identified. Demographic and phenotypic data was collected from the patients’ files. The NGS data was used as input for an in-house bioinformatics pipeline that identified and annotated variants, and resolved discrepant calls.

We have identified 79 potentially pathogenic variants in these patients that were not included in the genetic kit that tests for 30 mutations currently in use in South Africa. Of these variants, 18 passed in silico validation and were classified as high confidence calls. Four of the high quality calls were novel, 10 are known to cause CF, and four had no associated functional study. Using our methodology, we saw an increase in the mutation detection rate for each ethnic group in our cohort. The overall effect on the entire cohort was that the mutation detection rate more than doubled, going from 33% at the beginning of the study to 72% after application of our molecular biology and bioinformatics approach.


GEnE ExPRESSIOn PROFIlInG OF MYOCYTE CUlTURES IDEnTIFIES PERTURBED GEnE nETWORKS In OPHTHAlMOPlEGIC MYASTHEnIA GRAVIS

Melissa nel1, Sharon Prince2, Jeannine Heckmann1

1Neurology Research Group, Department of Medicine, University of Cape Town, Cape Town, South Africa, 2Division of Cell Biology, Department of Human Biology, University of Cape Town, Cape Town, South Africa

Background: While extraocular muscles are affected early in Myasthenia Gravis (MG), we have identified a distinct subphenotype of treatment-resistant ophthalmoplegia (OP-MG) which is frequently observed in patients with African-genetic ancestry. We speculate that OP-MG may result from aberrant responses in muscle damage/repair pathways, although the exact cause is unknown. A previous candidate approach identified 2 African-specific polymorphisms linked to OP-MG in the decay accelerating factor (DAF) and transforming growth factor beta-1 (TGFB1) genes. Using extended whole exome sequencing (WES) in an extreme sample of OP-MG vs control MG individuals, we discovered potentially pathogenic variants in DDX17, ST8SIA1, SPTLC3, IL6R which were sequence validated.

Objective: To assess WES and candidate gene expression differences between OP-MG and control MG using phenotype-specific muscle cell models.

Method: We developed differentiated ‘muscle’ models (OP-MG (n=10) vs control MG (n=6)) by forcing dermal fibroblasts to transdifferentiate into myocytes through transduction with an adenovirus expressing a MyoD transgene. To mimic patient-specific MG-induced muscle pathway responses, we stimulated the myocytes with homologous AChR-antibody positive MG sera. Gene expression in the ‘muscle’- and ‘MG’-disease models was assessed by quantitative PCR.

Results: Differential gene co-expression analysis identified differences between OP-MG and control MG myocytes. Strong correlations in expression levels of several gene pairs in both models were observed; in the MG model, ST8SIA1/DAF, ST8SIA1/TGFB1 and ST8SIA1/DDX17 were strongly correlated in control MG myocytes (r≥0.9; p<1x10-4) but not in OP-MG myocytes (r≤0.2). Gene expression arrays profiling >60 related genes are currently underway to more comprehensively examine gene pathways.

Conclusion: These results strongly suggest that the OP-MG candidate and WES genes function in a regulatory gene network which is tightly co-regulated in the control MG ‘muscle’ transcriptomes in response to MG sera. Preliminary results suggest that phenotype-specific gene variants may impact on myogenesis and ganglioside biosynthesis in extraocular muscle during MG leading to the synaptopathy in OP-MG.

Conclusion: These results strongly implicate the WES genes and previous OP-MG susceptibility variants as part of a gene co-expression network tightly co-regulated in the control MG ‘muscle’ transcriptomes in response to MG sera. Preliminary results suggest that phenotype-specific gene variants may impact on myogenesis and ganglioside biosynthesis in extraocular muscle during MG leading to the synaptopathy in OP-MG.


METABOBTT: A QUERYABlE CARDIOMETABOlIC DATABASE AnD WEB InTERFACE FOR THE BIRTH TO TWEnTY AnD METABOCHIP DATA

liesl Hendry1,2, Zané lombard3

1School of Molecular and Cell Biology, Faculty of Science, University of the Witwatersrand, Johannesburg, South Africa, 2Sydney Brenner Institute for Molecular Bioscience, University of the Witwatersrand, Johannesburg, South Africa, 3Division

of Human Genetics, School of Pathology, Faculty of Health Sciences, National Health Laboratory Service & University of the Witwatersrand, Johannesburg, South Africa

Advancements in technology, high-throughput experiments and multi-disciplinary research have resulted in a huge growth in the amount and complexity of biological data being generated in recent years. There is an increasing need for the development of databases to efficiently store and manage the data. Typically, publicly available datasets and the associated annotation data are accessed through internet-based browsers that offer a user-friendly interface to a database, which makes complex queries simple to execute. However, research project-specific data are not commonly stored in this way. The aim of this study was to develop a database which houses the phenotype (from the Birth to Twenty cohort), SNP annotation (for the Metabochip) and genetic association analysis data from a current project focused on identifying risk factors for cardiometabolic disease in South Africans. The relational database was developed in MySQL and an internet-based interface for the database was designed using PHP, HTML and CSS programming languages. Users can access the database from the web interface to generate summary statistics (basic and complex counts and average/minimum/maximum) on the phenotype data, download relevant phenotype, Metabochip and association analysis data that match certain user-supplied criteria and get information on how to work with genotype files in PLINK. The aim is for the data to be easily accessible and queryable by all members of the research group to ultimately accelerate biological knowledge discovery.


SICKlE CEll TRAIT (SCT) AnD AlPHA-THAlASSEMIA AnD TARGETED GEnOMIC VARIAnTS In CHROnIC KIDnEY DISEASE (CKD).

Tshepiso Masekoameng, Khutala Mnika, Collet Dandara, Ambroise WonkamUniversity of Cape Town, Cape Town, South Africa

Background: Sickle Cell and alpha-thalassemia in heterozygote states (taits) are two conditions that have the highest frequencies in sub-Sahanran Africa, due to the protective effect against the severest form of Malaria (Plasmodium falciparum). Beside the protection to malaria, heterozygocity of HbS and alpha-thalassemia have been said to be benign, but recent data, indicate an assocaition with Kidney dysfuctions in the USA; similar studies have not been investigated in Africa.

Objectives: This project aim to study the association between 1) Sickle cell trait (SCT), 2) 3.7 α-globin gene deletion trait, and 3) 26 targeted single nucleotide polymorphisms (SNPs) identifed in multiple GWAS studies, with Chronic Kidney disease (CKD) in an African Cohort.

Methods:Patients: 300 Cameroonian individuals (150 with CKD and 150 age and sex matched controls) will be investigated.Molecular Methods: 1) PCR-RFLP will be used to identify SCT, and 2) Gap-PCR the 3.7 alpha-globin gene deletion, and 3) MassArray / Tagman Assay and 4) followed by sanger sequencing in a subset of samples, to genotype the 26 targeted SNPs.

Statistical analysis: Descriptive statistics and logistics regression analysis will be performed to determine the significances of the associations.

Conclusions / Perpectives: The outcome of the study could have a major implicatiion for clinical surveillance for evetual kidnesy dysfunctions, of the millions of inviduals that carrier of sickle cell trait and 3.7 alpha-globin gene deletion. In addtion at-risk SNPs can possibly be used as proxy for anticipatory guidance in CKD.


REVIEW OF CHROMOSOMAl MICROARRAY TESTInG In THE POSTnATAl SETTInG AT TYGERBERG HOSPITAl

Heidre Bezuidenhout, Mike UrbanUniversity of Stellenbosch, Cape Town, South Africa

Background: Chromosomal microarray (aCGH) detect submicroscopic deletions and duplications and is the recommended first line genetic investigation for individuals with congenital anomalies and/ or developmental or intellectual disability; diagnostic yield of 15-20%, compared to conventional karyotyping 3%. There is limited information regarding the diagnostic yield, familial application, cost implications in the state sector in South Africa.Methods: Case series of patients with likely underlying genetic condition who had a diagnostic aCGH investigation, at Tygerberg Hospital, from 2012 to 2016.

Results: A total of 52 aCGH showed 33 normal results, 19 abnormal. Trios available in 11 cases. Further familial testing recommended in all but only performed in 9 cases. Re-evaluation of variants previously classified as having uncertain clinical significance now reveal clear phenotype with useful clinical application in a number of cases. A conclusive diagnosis directly influenced management planning in 9 cases. Average time until final diagnosis made by aCGH was 15 months. The phenotype characteristics that had the highest diagnostic yield will be analysed and presented. aCGH was typically performed as 2nd or 3rd tier investigation, with average of 2 genetic tests prior. Current MLPA testing would detect 4 cases. Information from cost-consequence analysis of two cases explores the rationale for use as first tier testing in future.

Conclusion:Diagnostic aCGH was not performed in any South African laboratory before 2016 limiting the clinical experience of geneticists with a standard care test. Its postnatal and prenatal clinical utility is well established internationally, and this study supports the routine postnatal diagnostic use in this setting. The next step is prenatal application as current recommendation by ACOG.


ExPERIEnCE OF THE FIRST ABnORMAl ARRAY CGH CASES In A DIAGnOSTIC SETTInG In SA

Sarah Walters1,2, Aliza Naude1, George Gericke1

1Ampath Trust, Centurion, South Africa, 2UKZN, Durban, South Africa

Array comparative Genomic Hybridization (aCGH) is a genetic technique which has recently been introduced locally in a private diagnostic laboratory in South Africa. It is currently being used in a post-natal setting for the detection of subtle structural chromosomal abnormalities not detected by conventional chromosome studies. We present ten cases, eight of which have been solved by aCGH technology.

Micro-array analysis was performed using the CGX v1.1 v1.1 8-plex array (Perkin Elmer) using the 60K oligonucleotide probes. Next-generation sequencing (NGS), multiplex ligand probe amplification (MLPA) and fluorescent in situ hybridisation (FISH) have been used as diagnostic confirmation.

A biased sample has been chosen to show the results obtained on the aCGH. One sample had a normal array result and was later shown to have an autosomal recessive single gene disorder on WES. Four cases have had confirmatory testing performed thus far by NGS, FISH and MLPA. One case had an array performed both locally and at an overseas site, results were comparable and their findings were confirmed by FISH. Confirmatory tests for the other cases are still in progress.

aCGH was initially developed in the 1990s and was designed for identifying sub-microscopic chromosomal deletions and duplications in tumour tissue. Development of this method has led to many previously unidentified chromosomal abnormalities being elucidated for other purposes. FISH, NGS and MLPA techniques assist in confirming the array results. aCGH is a vital laboratory technique for elucidation of with subtle chromosome abnormalities in previously undiagnosed cases.


DIAGnOSTIC TESTInG FOR MECP2-RElATED DISORDERS. A 12 YEAR REVIEW AT THE DIVISIOn OF HUMAn GEnETICS, nHlS, JOHAnnESBURG.

Elana Vorster1,2, Fahmida Essop1,2, Amanda Krause1,2, Kirstyn van Boeckel1,2

1National Health Laboratory Service (NHLS), Johannesburg, Gauteng, South Africa, 2University of the Witwatersrand (WITS), Johannesburg, Gauteng, South Africa

Rett syndrome (RTT) is an X-linked dominant neurological disorder which mainly affects females and forms part of the MECP2-related disorders. RTT is characterised by normal development for the first 6-18 months of life, followed by regression, specifically of motor and language skills. RTT is caused by mutations in the MECP2 gene and 72% of pathogenic mutations are found in a mutation hotspot region in exons 4.1 and 4.2. Deletions account for 32% of classical and 6.5% of atypical RTT cases and duplications have been linked to atypical RTT and intellectual disability in males. The aim of this study was to perform an audit of patients referred for RTT testing to the Division to determine the spectrum of MECP2 mutations identified and to investigate the presence of pathogenic copy number variations (CNVs) of MECP2 using the P015 SALSA MLPA kit. It was found that 20.6% (81/393) of patients referred for RTT testing (367 female, 26 male) had a pathogenic mutation in the hotspot region by sequencing analysis (19.1% (39/204) black, 21.4% (22/103) white, 28.6% (16/56) mixed ancestry and 13.3% (4/30) Indian). Eight novel variants were identified (6 black, 1 white, 1 mixed ancestry). More specifically, 15.4% (6/39) of variants identified in black patients were novel. Traditionally, further sequencing of MECP2, exons 2, 3 and 4.3 was offered to patients who tested negative for pathogenic mutations in the hotspot region but to date no mutations have been identified using this technique (0/26). MLPA was performed in 306 patients (280 female, 26 male) who previously tested negative for pathogenic mutations in the hotspot region, of which 5.9% (18/306) were found to have CNVs (7.3% (12/164) black, 3.8% (3/79) white, 5.7% (2/35) mixed ancestry and 3.6% (1/28) Indian). A specific CNV (c.(?_27)_(1051_?)del) accounted for 33.3% (4/12) of CNVs identified in black patients. Black South African individuals have been shown to have a diverse and unique genetic architecture. The pathogenicity of novel variants will be investigated using various online bioinformatics tools and by comparison with online mutation databases and the African Human Genome Variation Project. The combined pickup rate of sequencing of MECP2, exons 4.1 and 4.2 and MLPA is 25.6% (99/387). MLPA is recommended as a second tier test in patients clinically suggestive of RTT and who test negative for pathogenic mutations in the hotspot region.


GEnETIC VARIATIOnS In SDHD AnD TMEM127 In FAMIlIAl PARAGAnGlIOMA-PHEOCHROMOCYTOMA

Keleabetswe Mpye1, Bukiwe Peya2, Collet Dandara1, Ian Ross2

1Department of Pathology, UNIVERSITY OF CAPE TOWN, Cape Town Area, South Africa, South Africa, 2Department of Medicine, UNIVERSITY OF CAPE TOWN, Cape Town Area, South Africa, South Africa

Paragangliomas and pheochromocytomas are autonomic nervous system conditions characterized by the growth of benign tumors in paraganglia, groups of cells that are found near nerve cell bunches. Genetic mutations, sporadic or familial, in TMEM127, MAX or either subunit of succinate dehydrogenase (SDH) (A, B, C, D or F) complex have been linked to an increased risk of developing paraganglioma-pheochromocytoma. Familial paraganglioma-pheochromocytoma is inherited in an autosomal dominant pattern, only requiring a single copy of the altered gene to cause disease. Predisposition to developing familial paraganglioma-pheochromocytoma is passed on only if the altered copy of a gene is paternally inherited. Thus, we genotyped a family and extended family of paraganglioma-pheochromocytoma patient, with genetic variations in SDHD (c.305A>T; rs104894302) and TMEM127 (c.208G>A; rs121908819) genes, to assess the prevalence of the genetic variations in the family and calculate the risk of each family member to develop paraganglioma-pheochromocytoma. Clinical data revealed a history of carotid body tumor in the paternal family. Additionally, our preliminary genotype analyses show that the family may be at risk of developing the disease since all possess the pathogenic SDHD (c.305A>T; rs104894302) genetic variation that was most likely paternally inherited. All screened members carry the pathogenic heterozygous rs104894302 (c.305A>T) mutation in SDHD gene and only 3 carry both pathogenic heterozygous mutations in SDHD and TMEM127 genes. The predisposition risk of each family member will be statistically determined based on the genotype SDHD and TMEM127 genes.


DETERMInInG WHETHER SInGlE MlPA PROBE DElETIOnS ARE TRUE DElETIOnS OR FAlSE POSITIVE RESUlTS DUE TO MISMATCH PROBE BInDInG In PATIEnTS WITH

DEVElOPMEnTAl DElAY USInG SAnGER SEQUEnCInG

Quintin Goodyear1,2, Fahmida Essop1,2, Amanda Krause1,2

1NHLS, Johannesburg, Gauteng, South Africa, 2WITS, Johannesburg, Gauteng, South Africa

Developmental delay (DD) is defined by a delay in at least two functional domains such as language and cognitive abilities. The prevalence of DD in South Africa (SA) is estimated to be 3.6% of the population. Genetics is the cause for DD in more than half the cases. This can either be due to single gene effects or chromosomal abnormalities. The Division of Human Genetics in Braamfontein (NHLS, Johannesburg) screens patients with DD for copy number variations (CNVs) using Multiplex Ligation-dependant Probe Amplification (MLPA) kits: P245, P036 and P070. These kits are designed specifically for European populations and thus the probes may not be suitable for the unique SA genetic diversity, particularly for the black population. Single probe deletions could be due to true deletions or a result of mismatch probe binding influencing target amplification efficiency. The aim of the study was to determine if patients with a heterozygous single probe deletion had true deletions or sequence variants by using Sanger sequencing. Four unrelated black patients with single probe deletions in four different genes, RAI, EXT1, SNRPN and POLR3K were investigated. Various SNP databases were used to confirm if any identified variants were previously reported. Patients 1 (RAI1) and 4 (POLR3K) had previously reported SNPs identified in the probe binding regions. This resulted in mismatch binding for Patient 1, thus causing a false positive result. The SNP in patient 4 is unlikely to have resulted in a mismatch binding based on the MLPA result. No SNPs were identified in patients 2 (EXT1) and 3 (SNRPN) within the probe binding region. However, previously reported SNPs were found in an apparent homozygous state for patients 2, 3 and 4. This is supportive of the presence of a true deletion. Sanger sequencing successfully clarified the deletion status in the four patients tested. The study illustrates the need to be cautious when interpreting single probe deletion results obtained using commercially available MLPA kits which are not designed for the unique black SA population.


Wednesday 16 August 2017GEnOME InSTABIlITY In HUMAn COnGEnITAl DISORDERS

Chris Mathew

The connection between defects in DNA repair, which lead to genome instability, and human congenital disorders, has been established for many years. DNA repair defects often also cause predisposition to childhood or adult onset cancers. An exemplar of this connection is the chromosome breakage syndrome, Fanconi anaemia (FA), which is a mainly autosomal recessive disorder associated with microcephaly, radial ray abnormalities and structural defects of internal organs, but also with a very high risk of leukaemia and squamous cell cancers of the head and neck. In adults, heterozygosity for mutations in some of the many FA genes, such as BRCA2, confer an increased risk of breast and ovarian cancer. Recently, in a collaboration with the groups of Grant Stewart, Andrew Jackson and Fowzan Alkuraya, we showed that mutations in a hitherto orphan gene of unknown significance called DONSON, cause microcephalic dwarfism (Reynolds JJ et al, Nature Genetics 49: 537-549). Functional studies showed that DONSON encodes a protein which is critically important for mammalian DNA replication and genome stability. This work exemplifies the principle that the study of rare human genetic disorders can lead to important insights into basic pathways in mammalian biology.


A CHIlD WITH A HOMOZYGOUS MISMATCH REPAIR GEnE MUTATIOn In A lYnCH SYnDROME FAMIlY REVEAlS nOVEl InSIGHTS InTO CARCInOGEnESIS

Raj Ramesar, lindiwe lamola, Alvera Vorster, Ursula Algar, Paul GoldbergUniversity of Cape Town, Cape Town, South Africa

Introduction: In our research on Lynch syndrome, we have identified an extensive founder mutation in more than 300 individuals from 30 families, and the unusual occurrence of a child carrying the disease-causing mutation in a homozygous state. Unfortunately despite an expanded programme of surveillance, the child demised at the age of four years. This research is based on an extensive study of the genomic variants in the homozygous child compared to both her heterozygous parents and sibling.

Patients, Methods and Materials: This was the first time, ever, that we had considered genetic testing of children – in this instance of both parents who were affected with LS. The concern was that one of the children might be homozygous for the mutation and develop very early malignancies. Biological material was obtained from parents and the children with parental consent, and extensive genomic studies (i.e. exomes) were conducted in each of the four members of the nuclear family.

Results: Exome sequencing revealed that each of the family members had acquired of the order of 25 000 unique mutations in their exomes. In the process of mapping protein-protein interactions a number of pathways such as, WNT signalling, p53 pathway, and TGF-β were observed to be the most enriched pathways in the Mismatch Repair Deficient proband.

Discussion and Conclusion: A deficient mismatch repair environment, especially with heterozygous mutation carriers, and an exceptional case of a homozygous patient provides an excellent opportunity to understand the process of mutagenicity underlying the process of carcinogenesis. The extensive mutagenicity even between tissues of the same individual, pointed to an extraordinary susceptibility in individuals who are totally MMR deficient. Furthermore, the identification of de novo mutations in a range of genes, mutations in which are known to predispose to cancers, exposes possible pathways which will be included in future studies of cancers.


InVESTIGATInG CAnCER SUSCEPTIBIlITY GEnES In BlACK SOUTH AFRICAn BREAST CAnCER InDIVIDUAlS

Reabetswe Pitere1, Tasha Wainstein1, Fiona Baine1, Amanda Krause1,2

1University of the Witwatersrand, Johannesburg, South Africa, 2National Health Laboratory Service, Johannesburg, South Africa

Black South African breast cancer patients are reported to present with disease earlier in life and the disease tends to be more aggressive, with associated mortality increases in comparison to patients of European descent. The inheritance of breast cancer in black South African families is not fully understood. BRCA1 and BRCA2 deleterious mutations are the primary contributors to inherited breast cancer (IBC). Studies previously conducted in the Division of Human Genetics at the University of the Witwatersrand show that only about 10% of the Black patients carry either a BRCA1 or BRCA2 mutation. Further studies were warranted to determine what could be causing disease in the 90% of moderate- and high- risk patients without a BRCA mutation. The aim of this research project was to conduct a pilot study into the utility of a next generation sequencing (NGS) panel consisting of 26 genes to identify potentially pathogenic mutations in other inherited cancer susceptibility genes. Eighteen patients were screened and approximately 3000 variants were identified in total. Likely deleterious mutations were observed in genes such as ATM, BARD1 and RAD50. Nine previously reported variants of uncertain significance (VUS) were also identified. The findings from the study emphasise the need to move from single-gene to multiple-gene testing more especially in a population where minimal founder mutations have been identified. Furthermore, since BRCA mutations do not completely account for IBC in the black population, comprehensive testing in the form of a multi-gene panel is warranted for diagnostic use. Employing gene panels may aid in providing families with conclusive results regarding the disease and also, may improve the genetic counselling process.


Screening of high-risk BRCA1/2 mutation negative women for mutations in PALB2

nerina Chrisna van der Merwe, Mpoi Makhetha, Bhavini Kiran Dajee, Ines Buccamazza1University of Free State, Bloemfontein, South Africa, 2University of KwaZulu-Natal, Durban, South Africa

Introduction and aim: Women from high-risk families who tested negative for deleterious mutations within the high impact BRCA1 and BRCA2 genes, are four times more likely to develop breast cancer compared to women in the general population. Additional investigations involving BRCA negative families revealed various other role players such as PALB2. Germline inactivating mutations in this gene are associated with more than a four fold increase in risk for breast and ovarian cancer.

Methodology: Archived DNA samples of 46 BRCA1/2 negative high-risk BC patients were retrospectively selected based on the presence of a strong family history for the disease (>3 affecteds per family). All coding regions, together with splice-site boundaries were screened using High Resolution Melting Analysis (HRMA). Thirty primer pairs were optimized for the detection of variants. Samples that deviated from the baseline, were bi-directionally sequenced.

Results: A total of 26 variants have been detected, ranging from global polymorphisms to two likely pathogenic mutations. The majority of these variants were detected within exon 4, the largest coding region of the gene. The possible disease causing mutations were identified in an Indian patient with an extensive family history of breast cancer (PALB2 c.421C>T, p.Gln141Ter – rs886039686), with the second mutation being novel and detected in a patient of Mixed Ancestry (PALB2 c.508A>T, p.Arg170Ter).

Conclusion: This study confirmed the role of PALB2 as a breast cancer susceptibility gene, especially in high-risk BRCA1/2 negative patients. The results justify its inclusion in a more comprehensive breast and ovarian next generation sequencing cancer panel. Screening for mutations in PALB2 should be incorporated when screening for BRCA1 and BRCA2 as it might explain a significant percentage of familial breast and ovarian cancer in South Africa.


BRCA COUnSEllInG AnD TESTInG AT TYGERBERG HOSPITAl: 2008-2016

Mardelle Schoeman1,2, Justus P Apffelstaedt1,2, Karin Baatjes1,2, Mike Urban1,2

1Tygerberg Hospital, Cape Town, Western Cape, South Africa, 2Stellenbosch University, Cape Town, Western Cape, South Africa

Background: Tygerberg Hospital (TBH) is a resource-constrained tertiary hospital servicing a diverse population in the Western Cape. BRCA testing is based on pre-set criteria to new cases of breast cancer and ovarian cancer. Tests performed are tiered, with initial testing for locally common mutations, and subsequent comprehensive testing if indicated. We describe the TBH experience with BRCA counselling and testing.

Methodology: Review of records from the multidisciplinary clinics for breast or ovarian cancer, genetic counselling service, and BRCA laboratory testing between 2008-2016.

Results: The breast cancer service treated a total of 3900 new cases of female breast cancer between 2008 and 2016. Of these, 586 probands (15%) received BRCA testing, with numbers increasing steadily until 2011, after which testing per annum stabilised. A pathogenic mutation was detected in 86 (14,7%) of women tested and 2,2% of the entire cohort. Between 2014 and 2016, 11/15 probands with ovarian cancer receiving genetic counselling opted for BRCA testing. The detection rate in this small group was high (36%). Common “founder” mutations accounted for >70% of positive results. A genetic counsellor/clinical geneticist became more involved in the service offered in 2010, facilitating increased cascade testing: 44 at-risk family members were tested since, compared to 4 before this time.

Conclusion: The high detection rate for a common mutation panel illustrates its value as a first-line test in our resource-limited setting. BRCA testing in probands and family members increased with the involvement of a clinical geneticist/genetic counsellor. A multi-disciplinary approach with buy-in from all stakeholders is required for effective service-delivery.


THE GEnETIC HISTORY OF AFRICA

Carina Schlebush

In the last three decades, genetics played an increasingly important role in the inference of human history. Genetic studies provided conclusive information that helped to answer challenging questions, such as the “Out of Africa” migration of modern humans. Moreover, genetics helped to establish Africa as the birthplace of anatomically modern humans. The history of human populations in Africa is complex and includes various demographic events that influenced patterns of genetic variation across the continent. Several studies based on mitochondrial DNA, Y-chromosomes, autosomal markers and whole genomes contributed to unraveling the genetic sub-structure of African populations. Through these studies, it became evident the deepest population split among modern humans was between southern African Khoe-San populations and other African groups, while the central African Pygmy groups diverged subsequently from the common human lineage. Furthermore, it was shown that agriculture had a large influence on the distribution of current-day Africans and that West African agriculturist populations populated the whole of sub-Saharan Africa, replacing and/or assimilating former groups. Other farming groups from Northeast Africa, speaking Nilo-Saharan and Afro-Asiatic languages also expanded southwards and settled in East Africa, and perhaps as far as southern Africa, furthermore disrupting pre-existing population distributions. These later population movements complicate inferences regarding deep human history. With the increased availability of full genomic data from diverse African populations we will have more power to infer human demography and will especially try to address the complex aspects of deep human history. Furthermore, the first successful ancient DNA studies in Africa and the promise of many more African ancient DNA studies to come, will enable direct temporal comparisons – which will further contribute to unraveling deep human history on the African continent.

Suggested References• Campbell M, Hirbo J, Townsend J, Tishkoff SA (2014) The peopling of the African continent and the diaspora into

the new world. Current Opinion in Genetics & Development, vol 29, p120–132.• Gurdasani D, Carstensen T, Tekola-Ayele F, Pagani L, Tachmazidou I, Hatzikotoulas K, Karthikeyan S, Iles L,

Pollard MO, Choudhury A, Ritchie GR. The African genome variation project shapes medical genetics in Africa. Nature. 2015 Jan 15;517(7534):327-32.

• Lachance J, Vernot B, Elbers CC, Ferwerda B, Froment A, Bodo JM, et al, & Tishkoff SA (2012) Evolutionary history and adaptation from high-coverage whole-genome sequences of diverse African hunter-gatherers. Cell, 150(3), 457-469.

• Pickrell JK, and Reich D (2014) Toward a new history and geography of human genes informed by ancient DNA. Trends in Genetics, vol 30.9, p377-389.

• Schlebusch CM, Skoglund P, Sjödin P, Gattepaille LM, Hernandez D, Jay F, et al, & Jakobsson M (2012) Genomic variation in seven Khoe-San groups reveals adaptation and complex African history. Science, vol 338(6105), p374-379.

• Schlebusch CM, Malmström H, Günther T, Sjödin P, Coutinho A, Edlund H, Munters AR, Steyn M, Soodyall H, Lombard M, Jakobsson M. Ancient genomes from southern Africa pushes modern human divergence beyond 260,000 years ago. bioRxiv. 2017 Jan 1:145409.


An AnCESTRY InFORMATIVE MARKER PAnEl DESIGnED FOR AnAlYSInG STRATIFICATIOn In AFRICAn POPUlATIOnS

Dhriti Sengupta, Ananyo Choudhury, Michèle RamsayUniversity of the Witwatersrand, Johannesburg, South Africa

Ancestry Informative Markers (AIMs) are a subset of genetic markers that differ markedly in allele frequencies across different populations of the world. AIMs have been broadly applied to infer the bio-geographical ancestry and admixture proportions of a population or individual. While some AIM panels are designed with a focus on distinguishing the bio-geographic origin of individuals at a continental level, others estimate admixture proportions (e.g. in African Americans and Latino populations) and some examine the stratification of population ancestry in particular geographic areas (e.g. Europe and East Asia). Interestingly, in spite of the high genetic diversity among Africans, no AIM panel has been specifically designed for Africa. To address this, we have designed an AIM panel that can differentiate between the major ethnolinguistic groups (and subgroups) from Africa. Principal Component Analysis (PCA) was performed to assess the diversity of African populations from a merged 1000 Genomes Project (KGP), African Genome Variation Project (AGVP) and Schlebusch et al. 2012 dataset (~1725 African individuals). We grouped the populations into four clusters based on major ethnolinguistic divisions (Niger Kordofanian (NK), Khoesan, Afro-Asiatic and Nilo-Saharan); and seven groups based on the PCA clusters (Khoesan, Afro-Asiatic, Nilo-Saharan, South NK, East NK, Central west NK and West NK). Fst-based analyses were performed to identify the most differentiated SNPs (the candidate AIMs) for each pair of clusters. PCA based methods were applied to identify the optimal number of AIMs necessary to differentiate each pair of clusters. Next, we implemented a balancing algorithm which prioritizes AIMs based on Fst scores, number of clusters they differentiate and their ability to differentiate the closest clusters. We observed that less than 500 SNPs are sufficient to differentiate the four main ethnolinguistic groups within Africa and ~1000 additional SNPs are needed to resolve the NK subgroups, owing to their recent separation. These AIM panels were validated against both publicly available and novel African WGS datasets. Comparisons with randomly drawn SNP sets of the same size, as expected, showed that the panels performed substantially better in differentiating the clusters. The AIM panels can be used to refine genetic association studies and in applications where individual identity is required.


RUnS OF HOMOZYGOSITY In AFRICA: InSIGHTS InTO THE MORE COMPlEx PICTURE OF AFRICAn POPUlATIOn GEnETICS

Francisco Ceballos1, Michèle Ramsay1,2

1. Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa, 2Division of Human Genetics, School of Pathology, Faculty of Health Sciences, University of the

Witwatersrand, Johannesburg, South Africa

Through genetic structure analysis, admixture and principal components analysis it has been found Africa is the most genetically diverse region in the world. These studies have also shown that recent population movements and expansions acted as a homogenizing force causing modest to low differentiation among populations representing the major sub-populations. However, this may not be the complete picture, a different approach and outcome can be achieved by analyzing genome-wide homozygosity through Runs of Homozygosity (ROH). ROH are contiguous regions of the genome where an individual is homozygous across all sites. These runs can arise through different mechanisms with inbreeding being the most common. ROH are ubiquitous because of a phenomenon known as pedigree collapse. Analyses of ROH provide insights into the understanding of human demographic history and deciphering the genetic architecture of complex diseases.

We analysed ROH in over 2800 individuals from the African Genome Variation Project and the 1000 Genomes Project, to study demographic events like bottle necks and low effective population size, as well as other types of sub-population structure caused by cultural practices like consanguinity. We found that populations from West Africa and the Horn of Africa have inbreeding levels (FROH) similar to those in India and Latin America (West and Horn of Africa FROH=0.0082 and 0.0086, India and Latin-American populations FROH=0.0088 and 0.0098). ROH size distribution showed that African populations generally have more long ROH (>8Mb) and fewer short ones (<1Mb), in comparison with other world populations, suggesting recent inbreeding and consanguineous practices. However, some Horn of Africa populations showed higher number of shorter ROH than populations in the rest of Africa, pointing to the historic facts that in the past these populations had smaller effective population sizes. Examining the genomic distribution of ROH identified ROH islands (ROHi) where homozygous windows in particular locations are shared by more than 10% of the population. African populations have on average 194 ROHi scattered throughout the genome. A single ROHi can be up to 5Mb long, but the most common are between 1 to 0.5 Mb. ROHi highlight candidate positions for selection foot prints and other genomic features.


APPEARAnCE AnD REAlITY: UnPACKInG RACIAl PROFIlInG

Himla SoodyallNHLS/WITS, Johannesburg Area, South Africa, South Africa

In a country where the lived experience of people is inextricably bound with social categorisation, particularly ‘race’, and its association with power, inequality, discrimination, poverty and injustice, there is a pressing need to build a cohesive society which underscores redress and reconciliation. Section 9 of the Constitution of South Africa (Constitution 1996) embodies such values and avows to protect all individuals against unfair discrimination on one or more grounds, including race, gender, sex, pregnancy, marital status, ethnic or social origin, colour, sexual orientation, age, disability, religion, conscience, belief, culture, language and birth.

However, as we move deeper into our democracy, many South Africans still battle to construct a sense of belonging, especially when issues around race continues to be dominant in public discourse. For many, the meaning of ‘race’ refers to phenotypic traits or observable characteristics such as skin colour, facial features, hair texture, etc. Even though science has confirmed that patterns of human variation exist, it has also provided ample evidence that there is no biological or genetic basis for race and that it is socially constructed.

It is timely that we as the genetics community of the country engage with and educate the general public on how evolutionary processes have contributed in shaping human variation and to demystify issues around race and other prejudices that plague our society.


PHARMACOGEnETICS OF TEnOFOVIR

Kagisho Montjane1, Elizabeth Kampira3, Ambroise Womkam2, Collet Dandara4

1University Of Cape Town, Cape Town,Western Cape, South Africa, 2University Of Cape Town, Cape town, Western Cape, South Africa, 3University of Malawi, Blantyre,Blantyre District, Malawi, 4University Of Cape Town, Cape Town,Western Cape,

South Africa

Background: HIV and Aids is a pandemic disease with Africa carrying the highest burden. Tenofovir (TDF) is used as combination antiretroviral in the treatment and prevention of HIV. TDF is not metabolised but transported by proteins coded for by polymorphic genes. Interpatient variability in TDF drug disposition has been observed and genetic factors are thought to play an important role in this variability. Single nucleotide polymorphisms (SNPs) have been reported in transporter genes among Caucasian and Asian populations, however, their distribution in African populations is poorly understood. The aim of this study is to investigate the role of genetic variation in transporter coding genes on the response to tenofovir among Southern African populations.

Method: Four hundred (n=400) Malawian, Zimbabwean and South African HIV/AIDS patients on TDF will be analysed. We will evaluate 20 SNPs in genes associated with TDF transport using Taqman Assays, PCR-RFLP, SNaPshot and Sanger sequencing, as may be appropriate. The frequencies of these SNPs will be analysed with different statistical tools to determine their role in TDF response among patients.

Conclusion: The aim of the study is to understand effect of generic variation of transporter genes on TDF patients in SSA. The ultimate aim will be to find out if pharmacogenetics can be used to identify, before treatment, which patients are likely to present with adverse drug effects.


KIllER CEll IMMUnOGlOBUlIn-lIKE RECEPTOR (KIR) GEnE COnTEnT VARIATIOn InFlUEnCES IMMUnE ACTIVATIOn In AnTIRETROVIRAl THERAPY nAïVE ADUlT

ZIMBABWEAnS

Kudakwashe Mhandire1,4, lynn Zijenah1, louis-Marie Yindom2, Kerina Duri1, Babill Stray-Pedersen3, Collet Dandara5

1University of Zimbabwe, Harare, Zimbabwe, 2Nuffield Department of Medicine, University of Oxford, Oxford, UK, 3University of Oslo and Womens’ Clinic, Rikshospitalet, Oslo, Norway, 4Letten Foundation Research House, Harare, Zimbabwe, 5University of

Cape Town, Cape Town, South Africa

KIR gene variants modulate HIV disease progression through regulation of natural killer (NK) cell response to infection. However, it is unclear whether inter-individual variation in KIR gene content influences chronic immune activation (IA), a feature of HIV-infection that is associated with poor prognosis. IP-10 is a cytokine secreted by immune cells following infection with HIV which is widely regarded as a marker of IA. Thus, we investigated the association between KIR gene content variation and plasma IP-10 concentration in 177 HIV-infected, but ART-naive black Zimbabweans. Presence/absence of 15 KIR genes was determined using sequence specific primer polymerase chain reaction. In addition, plasma IP-10 was quantified using ELISA. Plasma IP-10 concentrations were compared between KIR gene carriers and non-carriers using Mann-Whitney ranksum test. KIR2DL3 gene was associated with elevated IA as IP-10 concentrations were significantly higher in KIR2DL3 carriers (265.20 [179.99-385.19]) and in KIR2DL3/KIR2DL3 homozygotes (263.37 [174.98-404.83]) than in non-KIR2DL3 carriers (183.56 [110.98-230.81]), p=0.001 and KIR2DL2/KIR2DL2 homozygotes (p=0.003), respectively. Similarly, IP-10 concentrations were significantly higher in the KIR3DS1+ group (313.86 [230.05-469.20]) than in the KIR3DS1- group (246.01 [169.58-373.32]), p=0.030. The remaining 13 genes were not associated with plasma IP-10 concentrations. We identify novel association between carriage of KIR2DL3 and KIR3DS1 genes, and IA estimated by high plasma IP-10 concentrations in ART-naïve adults. KIR2DL3 and KIR3DS1 genes promote robust NK cell response to HIV infection through NK cell licensing and stimulation of the activation pathway, respectively. Thus, carriage of the genes may enhance HIV-associated IA.


THE COnSEQUEnCE OF TERMInOlOGY RElATED TO COnGEnITAl DISORDERS

Helen Malherbe1, Matthew Darlison2, Arnold Christianson3

1School of Clinical Medicine, College of Health Sciences, University of KwaZulu Natal, KwaZulu Natal, South Africa, 2WHO Collaborating Centre for Community Genetics, Centre for Health Informatics and Multiprofessional Education (CHIME),

University College London, London, UK, 3Wits Centre for Ethics (WiCE), University of the Witwatersrand, Gauteng, South Africa

The lack of global consensus on terminology related to congenital disorders (CDs) has led to confusion both in the medical genetics - and wider medical and scientific community. The use of disparate and non-equivalent terms, often referring to specific groups of CDs has prevented the comparison of surveillance datasets both nationally and internationally.

Terms describing sub-sets of CDs, most commonly ‘congenital anomalies’ which excludes 40% of CDs (mainly single gene disorders), are often used to erroneously represent the totality of CDs. Since only a portion of CDs are being reported, this prevents the contribution of CDs to the disease burden from being comprehensively and accurately evaluated through empiric data. This underestimated contribution of CDs to infant and child mortality diminishes the required political will, resulting in inadequate services for those affected by, and at risk of CDs, particularly children and those living with disability.

Although efforts by the World Health Organization (WHO) in 2006 resulted in international agreement on the definition and usage of the terms ‘congenital disorders’ and ‘birth defects’, there has been limited uptake of these synonymous terms, both globally and in South Africa. Many scientific studies continue to use disparate terms, often omitting a formal definition of the terms used and specific conditions included.

It is proposed that a more structured system of terminology be developed, and each term be formally coded and linked to specific known system entities, such as the International Classification of Diseases (ICD-10 or subsequent revision) or other relevant system. This would enable the specific CDs included in a dataset to be identified and may be a valuable tool enabling data comparison and a more accurate assessment of the impact of CDs on the disease burden. This, in turn, would contribute to improved medical genetic services for those affected and at risk of CDs.


BEnCH TO BEDSIDE GEnETICS

Richard Hift

A close collaboration between laboratory and clinician is of critical value in many fields of medicine, and in genetics more than most. Cooperation between the laboratory-based scientist and the clinician has proven critical to the development of the diagnostic and therapeutic approaches on which successful management of patients is based. Such cooperation is particularly fruitful when the clinician and the non-clinical scientist have an excellent and intuitive understanding of each other’s fields.

In this talk this is illustrated by three examples based on inherited disorders of haem synthesis, the porphyrias. Protoporphyria long presented a puzzle, since the pattern of inheritance conformed with neither a typical autosomal recessive nor dominant pattern; indeed it was often termed “pseudo-dominant”. This was subsequently explained as the result of co-inheritance of a recessive gene in trans-to a common polymorphism associated with reduced gene expression. A new twist has been the more recent identification of a clinical disorder almost identical in clinical presentation to protoporphyria, but where the mutation besides on a different gene on the X chromosome with a completely different function. Furthermore this gene already has a well-characterised association with a very different group of genetic disorders, X-linked sideroblastic anaemia. The deviation from the normal clinical consequences of inheritance of these X-linked mutations and their convergence with protoporphyria is dependent on a gain of function.The second is with reference to the so-called Royal malady: the suggestion that the British Royal family carry a gene for variegate porphyria (the commonest monogenetic disorder in South Africa), and that this might have had an important role in history, being responsible for the insanity and erratic rule of King George III, during whose reign Britain lost the American colonies. Yet a disciplined scientific approach based on an understanding of the limitations of diagnosis based on clinical considerations alone and appropriate use of a population genetics approach, combined with Bayesian analysis, should lead to an emphatic rejection of this hypothesis.

The third is in terms of therapy. The porphyrias are a heterogeneous group of disorders. Advances in understanding of these disorders at the molecular level has permitted the development of a number of therapeutic approaches, ranging from the coarse (whole organ transplantation) to gene replacement, gene modification and siRNA-based therapy.


poSterS0001 Boerhavia diffusa and Hyptis suaveolens herbal extracts inhibit CYP1A2, CYP29 and CYP3A4 as

well as trigger Go/G1 cell cycle arrest: implications for pharmacogenomicsNICHOLAS EKOW THOMFORD1,2, KEVIN DZOBO3,4, AMBROISE WONKAM1, COLLET DANDARA1, 1Pharmacogenetics Research Group, Division of Human Genetics, Department of Pathology and Institute of Infectious Diseases and Molecular medicine, Faculty of Health Sciences, University of Cape Town, CAPE TOWN, South Africa, 2School of Medical Sciences, University of Cape Coast, CAPE COAST, Ghana,

3International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, CAPE TOWN, South Africa, 4Division of Medical Biochemistry and Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, CAPE TOWN, South Africa

0002 Clinical and Genetic Predictors of Pain in Sickle Cell Disease PatientsKhuthala Mnika1, Gift Pule1, Emile R Chimusa1, Collet Dandara1, Ambroise Wonkam1,2, 1University of Cape Town, Cape Town, South Africa, 2Department of Medicine, Cape Town, South Africa

0008 Young adults’ perceptions of the implications of their hereditary visual impairment: A Cape Town based study.Kalinka Popel1, Jacquie Greenberg1, Cordelia Leisegang1, Gill Dusterwald1, 1University of Cape Town, Western Cape, South Africa

0009 Molecularly confirmed Vascular Ehlers Danlos syndrome in a South African patientCandice Feben1,2, Jennifer Kromberg2, Amanda Krause1,2, 1National Health Laboratory Service, Johannesburg, Gauteng, South Africa, 2University of the Witwatersrand, Johannesburg, Gauteng, South Africa

0013 SCREEnInG FOR THE PRESEnCE OF SInGlE nUClEOTIDE POlYMORPHISMS ASSOCIATED WITH TYPE 2 DIABETES MEllITUS In A BlACK SOUTH AFRICAn POPUlATIOnGertruide Marx1, Lerato Diseko2, 1University of the Free State, Bloemfontein, South Africa, 2NRF, Bloemfontein, South Africa

0014 A novel investigation of the role of DRD2 and DRD4 genetic polymorphisms and personality traits with concussion riskShameemah Abrahams1, Sarah Mc Fie1, Miguel Lacerda2, Jon Patricios3,4, Jason Suter5, Alison V September1, Michael Posthumus1, 1Division of Exercise Science and Sports Medicine, Department of Human Biology, Faculty of Health Science, University of Cape Town, Cape Town, South Africa,

2Department of Statistical Sciences, Faculty of Science, University of Cape Town, Cape Town, South Africa, 3Morningside Sports Medicine Clinic, Johannesburg, South Africa, 4Section of Sports Medicine, University of Pretoria, Pretoria, South Africa, 5Sports Science and Exercise Medicine Clinic, Cape Town, South Africa

0022 Endocrine Profiling in Black South African Fanconi Anaemia Patients, Homozygous for a FANCG Founder Mutation.Bronwyn Dillon1,2, Candice Feben1,2, Amanda Krause1,2, David Segal1,3, Rosalind Wainwright1, Janet Poole1, Engela Honey4, 1The University of the Witwatersrand, Johannesburg, South Africa, 2National Health Laboratory Service (NHLS), Johannesburg, South Africa, 3The Wits Donald Gordon Medical Centre, Johannesburg, South Africa, 4The University of Pretoria, Pretoria, South Africa

0024 Bacterial expression of recombinant ACSM2A and ACSM2B proteins and optimization of a suitable enzyme test.Phillip Venter1, Rencia van der Sluis1, 1North-West University, Potchefstroom, North West, South Africa

0028 Investigation of Parkin-mediated ubiquitination of Mycobacterium tuberculosis using Confocal MicroscopyVictoria Cole1, Glynis Johnson1, Craig Kinnear1, Lize Engelbrecht2, 1Stellenbosch University, Cape Town, South Africa, 2Central Analytical Facilities, Cape Town, South Africa

0031 Association of lipid levels with genetic variants in four familial hypercholesterolaemia genes in sub-Saharan African populationsMahtaab Hayat1,2, Michele Ramsay1,2, Robyn Kerr1, 1Division of Human Genetics, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, Gauteng, South Africa,

2Sydney Brenner Institute for Molecular Bioscience, University of the Witwatersrand, Johannesburg, Gauteng, South Africa


0032 The role of opioids in the management of chronic pain in South African breast cancer survivors Firzana Firfirey1, Lara Brookstein3, Zinhle Radebe3, Nicole Stewart3, Helen Worthington-Smith3, Alison September1, Delva Shamley1,2, 1Div. Exercise Science and Sports Medicine, University of Cape Town, Cape Town, Western Cape, South Africa, 2Clinical Research Centre, University of Cape Town, Cape Town, Western Cape, South Africa, 3Div. Physiotherapy,University of Cape Town, Cape Town, Western Cape, South Africa

0036 Retrospective Audit of Chromosomal Microarrays Performed by the Division of Human Genetics, at External laboratories, 2011-2016Lindsay Lambie1, Amanda Krause1, 1Division of Human Genetics, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand; National Health Laboratory Service, Johannesburg, South Africa

0040 Congenital central hypoventilation syndrome: A rare cause of recurrent neonatal apnoeaLiani Smit1, Leonore Greybe2, Jacomina (Mimi) Du Preez2, Michael Urban1, 1Division of Molecular Biology and Human Genetics, University of Stellenbosch / Tygerberg Hospital, Western Cape, South Africa,

2Department of Paediatrics, University of Stellenbosch / Tygerberg Hospital, Western Cape, South Africa

0044 Stop Birth Defects - Bloemfontein women’s perspective on warfarin and pregnancyMaureen Conradie1, Chantel van Wyk1, Bertram D. Henderson1, 1University of the Free State, Bloemfontein, South Africa

0046 Incorporating distance learning in Genetic Counselling training – Is it possible on the African Continent?Tina-Marie Wessels1, Jacquie Greenberg1, 1Division Human Genetics, University of Cape Town, Cape Town, South Africa

0052 Comparison of the relative enzyme activity of three glycine N-acyltransferase haplotypes: S156, T17S156 and S156C199Chantelle Schutte1, Rencia van der Sluis1, 1North-West University, Potchefstroom, South Africa

0055 A unique DnA sample collection of South African Parkinson’s disease patientsMonique Stemmet1, Soraya Bardien1, 1Stellenbosch University, Cape Town, Western Cape, South Africa

0056 Metabochip study reveals novel insight about genetic risk and heritability of obesity in black South AfricansVenesa Sahibdeen1, Liesl Mary Hendry2,5, Ananyo Choudhury2, Nigel J Crowther3, Himla Soodyall1, Michele Ramsay2,1, Shane A Norris4, Zane Lombard1, 1Division of Human Genetics, School of Pathology, Faculty of Health Sciences, National Health Laboratory Service & University of the Witwatersrand, Johannesburg, South Africa, Gauteng, South Africa, 2Sydney Brenner Institute for Molecular Bioscience, University of the Witwatersrand, Johannesburg, South Africa, Gauteng, South Africa, 3Department of Chemical Pathology, National Health Laboratory Service & University of the Witwatersrand, Johannesburg, South Africa, Gauteng, South Africa, 4MRC/Wits Developmental Pathways for Health Research Unit, Department of Paediatrics, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Afric, Gauteng, South Africa, 5School of Molecular & Cell Biology, Faculty of Science, University of the Witwatersrand, Johannesburg, South Africa, Gauteng, South Africa

0063 METHYlATIOn SPECIFIC-MlPA TECHnIQUE FOR DIAGnOSIS OF GEnETIC DISORDERS WITH A DEFECT In IMPRInTInG GEnESOdirile Tabane1,2, Fahmida Essop1,2, 1National Health Laboratory Services, Braamfontein, South Africa,

2University of the Witwatersrand, Johannesburg, South Africa

0065 Interrogating the role of genes functioning in the angiogenesis pathway on Achilles tendinopathy riskMasouda Rahim1, Colleen Saunders2, Andrea Gibbon1, Louis El Khoury3, Stuart Raleigh4, William Ribbans4, Malcolm Collins1, Junaid Gamieldien2, Michael Posthumus1, Alison September1, 1Division of Exercise Science and Sport Medicine, University of Cape Town, Cape Town, South Africa, 2South African National Bioinformatics Institute, University of the Western Cape, Cape Town, South Africa, 3Department of Biochemistry and Molecular Biology, Mayo Clinic, Minnesota, USA, 4Division of Health and Life Sciences, University of Northampton, Northampton, UK

0066 Assessment of maternal-infant bonding between mothers and their babies with a cleft lip.Elzette Nienaber1, Merlyn Glass2, Lindsay Lambie2, 1University of the Witwatersrand, Johannesburg, South Africa, 2National Health Laboratory Service, Braamfontein, Johannesburg, South Africa


0067 Mutation detection in the Endoglin gene in a family affected with hereditary haemorrhagic telangiectasiaKimberly Peta1, Gerda Marx1, 1University of the Free State, Bloemfontein, South Africa


0069 Idiopathic dilated cardiomyopathy (IDCM) – determining whether African and South African individuals have evidence of familial diseaseClaude Bailly1, Amanda Krause1, Sasha Henriques1, 1WITS, Johannesburg, South Africa


0071 Delineation of a tetrasomy 9p caused by a pseudodicentric 9p using three genetic testing methodsSarah Walters1,3, Lindsay Lambie2, 1Ampath Trust, Centurion, South Africa, 2NHLS, Braamfontein, South Africa, 3UKZN, Durban, South Africa

0072 Variants identified in families with cerebral cavernous malformationIlse Crous1, Tina-Marie Wessels1, Nico Enslin2, Karen Fieggen1, 1University of Cape Town, Cape Town, South Africa, 2Red Cross Children’s Hospital, Rondebosch, South Africa

0080 MUTATIOnS In BlOOM’S SYnDROME: DO THEY COnTRIBUTE TO FAMIlIAl BREAST CAnCER RISK In SOUTH AFRICAnS?Johnathan Adams1, Nerina Chrisna van der Merwe1,2, Sue-Rica Schneider3, Ines Buccamazza4, Evgeny Imyanitov5, 1Division of Human Genetics, University of the Free State, Bloemfontein, Free State, South Africa, 2Division of Human Genetics, National Health Laboratory Services, Bloemfontein, Free State, South Africa, 3Department of Genetics, University of the Free State, Bloemfontein, Free State, South Africa, 4Department of Surgery, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, KwaZulu-Natal, South Africa, 5Prof. N.N.Petrov Research Institute of Oncology, St. Petersburg, Pesochnyy, Russia

0081 Addressing Cancer Treatment in an African Setting: A Bioinformatics Analysis of Pharmacogenomically Relevant VariantsJorge Da Rocha1,3, Zane Lombard1,2, Michele Ramsay1,3, 1University of the Witwatersrand, Johannesburg, South Africa, 2National Health Laboratory Service, Johannesburg, South Africa, 3Sydney Brenner Institute for Molecular Bioscience, Johannesburg, South Africa

0083 InVESTIGATInG THE ROlE OF CETP GEnETIC VARIATIOn In DYSlIPIDEMIA AMOnG BlACK SOUTH AFRICAnSJonathan Evans1, Donald Tanyanyiwa1, Collet Dandara1, 1University of Cape Town, Cape Town, South Africa

0086 Pharmacogenomics of warfarin: the role of genetic variation in VKORC1, CYP4F2 and GGCx on maintenance dose Zinhle Cindi1, Mpiko Ntsekhe1, Edson Makambwa1, Keleabetswe Mpye1, Collet Dandara1, 1University of Cape Town, Cape Town, South Africa

0087 TP53 sequence variants in intestinal-type gastric cancer of South African patientsLesibana Sema1, Carina da Silva1, Cecilia Dorfling1, Elizabeth van Rensburg1, 1Department of Genetics,University of Pretoria, Pretoria,Gauteng, South Africa

0095 Assessing the utility of a heritable connective tissue panel in a resource constrained setting.Rizqa Sulaiman-Baradien1,2, Ambroise Wonkam1,2, Karen Fieggen1,2, Nakita Laing2, 1University of Cape Town, Cape Town, South Africa, 2Groote Schuur Hospital, Cape Town, South Africa

0096 Founder Mutations in black South Africans: clinical importance and utilityHeather Seymour1, Michele Ramsay1,3, Amanda Krause1,2, 1University of the Witwatersrand, Johannesburg, South Africa, 2National Health Laboratory Services, Johannesburg, South Africa, 3Sydney Brenner Institute for Molecular Bioscience, Johannesburg, South Africa

0097 PREVAlEnCE AnD PATTERn OF COnSAnGUInEOUS MARRIAGE In nORTH WEST MOROCCOHouria Hardouz1, Hinde Hami1, Abdelrhani Mokhtari1, Abdelmajid Soulaymani1, Ali Quyou1, 1Laboratory of Genetics and Biometry, Faculty of Science, Ibn Tofail University, Kenitra, Morocco


0098 Investigation of Genetic modifiers that result in different phenotypes in heterozygous females with xlRP mutationsTshegofatso Pelego1, Lisa Roberts1, Raj Ramesar1, 1University of Cape Town, Cape Town, South Africa

0099 Exploration of the impact of genetic counselling and patient support group involvement on inherited retinal degenerative disorders patients: a qualitative studyRene Goliath1, Jacquie Greenberg1, Tina Marie Wessels1, 1Division of Human Genetics, Department of Pathology, MRC/UCTResearch Unit, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa

0101 Exome sequencing in South Africa: stakeholder views on feedback of individual research results and incidental findingsNicole van der Merwe1, Jantina De Vries1, Rajkumar Ramesar1, 1University of Cape Town, Cape Town, Western Cape, South Africa

0104 Developing focused genetic diagnostic approaches for developmental delay in South AfricaNadia Carstens1, Zane Lombard1, Amanda Krause1, 1Division of Human Genetics, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, Gauteng, South Africa


Shire SA NP00607/2017

Shire Pharmaceuticals South Africa (Pty) Ltd. Regus Johannesburg, The Campus c/o Sloane and Main Road, Bryanston, 2021.

Co Reg. 2016/ 430880/ 07. www.shire.comTel: +27 (0)64 255 7929www.shire.com

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HAEMATOLOGY

IMMUNOLOGY NEUROSCIENCE

GI/ INTERNAL MEDICINE ONCOLOGY

GENETIC DISEASES

Fabry DiseaseGaucher DiseaseHunter SyndromeHereditary Angioedema

Immune DeficienciesCritical CareNeurological & Pulmonary Disease

Short Bowel SyndromeHypoparathyroidismUlcerative ColitisEoE2

CMV2

Crohn’s2

IBD2

Haemophilia A & BHaemophilia with Inhibitorsvon Willebrand Disease Essential Thrombocythemia

Acute Lymphoblastic LeukemiaPancreatic Cancer

ADHDBinge Eating DisorderEpilepsy1

Hunter Syndrome IT2

Hunter Syndrome CNS2

Neuromyelitis Optica2

(1) Preclinical program (2) Pending regulatory approval


Go digital with Discovery | HealthID Coordinated care made easier

HealthID gives you fast, up-to-date access to your patients’ health information, which facilitates the efficient coordination of patient care, enabling better patient outcomes.

It also reduces administration by assisting with online applications, scripting and referrals.

Discovery Health (Pty) Ltd; registration number 1997/013480/07, an authorised financial services provider and administrator of medical schemes.

Download the HealthID app from App Store or visit www.discovery.co.za

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FROM EXTRACTION TO ANALYSIS GENOMICS SOLUTIONSTHAT GO WHERETHE SCIENCE LEADS

Generating accurate, reproducible results efficiently is top of mind in everyone’s genomic lab. And the answer is applications expertise, up and down the workflow – from extraction to analysis. With our chemagic™ extraction technology, fully integrated automated library prep, robust sequencing chemistries, sample quality quantitation, visualization and analysis of complex sequencing data, and much more, we help you deliver top-quality samples for your world-class research. PerkinElmer genomics solutions: Wherever your science leads, we’ll be there.

For Research Only. Not for use in diagnostic procedures.


Sanofi-Aventis South Africa (Pty) Ltd, Sanofi-Aventis House, 44 on Grand Central Office Park, 2 Bond Street, Grand Central Ext 1, Midrand 1685. Reg. no: 1996/010381/07.

FOCUSED ON DEVELOPING SPECIALTY TREATMENTSfor debilitating diseases that are often diffi cult to diagnoseand treat, providing hope to patients and their families.

programme, abstracts & floor plan · page 3 abstracts of the 17th biennial congress of the...

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