Provision of Genetic Counselling for Patients with

Retinal Dystrophy Prof. Graeme Black, Ms Georgina Hall

Depts. of Ophthalmology and Clinical Genetics,

Manchester

Causes of childhood blindness

Africa S America India

Genetic 21% 30% 30%

Intrauterine 7% 2% 10%

Perinatal 2% 2% 20%

Childhood 34% 37% 12%

Unknown 35% 30% 27%

Developed countries30-50% childhood visual handicap is genetic

Developing countries

In developed countries,

hereditary causes of blindness

are the most important cause of

childhood visual handicap

Retinitis pigmentosa

Symptoms• night blindness• constriction of peripheral

visual field • later loss of central vision.

Diagnosis • Progressive photoreceptor

dysfunction • undetectable / reduced ERGs……

rod-mediated responses more severely affected than cone-mediated (i.e. rod-cone dystrophy).

Retina • pigment in bone-spicule distribution.

Retinitis pigmentosa

1 in 2500

Genetic condition

Caused by single fault in one gene

Deoxyribonucleic acid (DNA) and chromosomes

46 chromosomes Human chromosomes

carry 20,000 to 30,000 genes

Genes and Inheritance

Chromosomes – 22 identical pairs (“Autosomes”)– 1 pair non- identical (“Sex

Chromosomes”)XX=Female XY=Male

Each chromosome carries 1 copy of gene (ie 2 copies of a gene per pair)

A genetic disorder is caused by

a single faulty gene

What is a gene?

Gene

Protein

Classification of RP Genetic

– Autosomal dominant 10-15%– X-linked 5-15%– Autosomal recessive 30-50%– Sporadic 20-50%

Onset– Birth : Leber congenital amaurosis– Childhood : many X-Linked, AR forms– Later onset: some AD forms

Retinal manifestations

(Symptoms or ERG define)

– Cone-rod dystrophy– Rod-cone dystrophy– Cone dystrophy– Rod dystrophy

Genes and RP

Confusing

– Faults in a large number of genes can cause RP and retinal degeneration

Retinal dystrophies Hugely variable

– onset outcome retinal findings– gene defect inheritance pattern

Gene analysis tells us there are a large number of different forms - ?100 -200

Majority unclassifiable clinically

Increasingly the precise genetic defect is known for many retinal degenerations…… or rather could be known

Genetics and Ophthalmology in Manchester

– 8 clinics per month– Run by clinical genetics alongside

ophthalmology– Coworkers present– Held in clinical genetics unit / eye hopsital– 4-6 pts/clinic

• Time• examine family members

– Letters to patient

Why have a genetic ophthalmic clinic at all?

Large group of uncommon disorders– Unified approach – Diagnosis– Investigation– Counselling / FH Issues

Pts referred for specialist opinion– ?correct diagnosis– ?geneticists cannot examine

Clinician’s Objectives

Diagnosis

Risk estimation to family members Screening requirements Information Support

Patient’s objectives (I think….) Treatment

Prognosis Understanding Risks to family members (Children)

– Prenatal diagnosis Presymptomatic diagnosis

Perhaps our objectives are different….

Genetic Counsellors

MSc genetic counselling Nurses

– Additional training in genetics and counselling 300 in the UK Professional body (AGNC) Register (GCRB)

– Code of ethics / conduct– Competency assessment

What is “genetic counselling”

Communication processComprehend medical informationAppreciate the hereditary impactFacilitate decision making (genetic testing, reproduction) in context of beliefs / family / cultural sensitvityMake best possible adjustment to genetic condition in family

Why do people request genetic counselling?

Diagnosis What is the cause? What will it mean for me? What are the risk to my children (other

family members) What screening / tests / treatments

available

Nature of genetic information

Patients may need to absorb a lot of new information that is often complex, abstract and difficult to grasp.

Rapid advances in understanding of genetic basis of eye conditions.

Heterogeneity – inheritance not clear cut.

Counselling issues

Over and above emotional impact of visual impairment (grief, loss)

Burden / guilt Coping with risk / uncertainty Difficult decisions Impact on relationships / family dynamics Family coping styles / beliefs around visual

impairment

X-linked retinitis pigmentosa

Boys affected late childhood / early teens Progressive No treatment Faulty gene on X chromosome Mothers are “carriers”

– Half daughters will be carriers– Half sons will be affected

XL Retinitis Pigmentosa

5

3

3

L dropped out of school, no exams Diagnosed XLRP aged 17 Anger and depression Isolated

M denied diagnosis. “It hasn’t come from me”

?guilt

XL Retinitis Pigmentosa

5

3

3

Am I a carrier?S

guilt

Sister S wanted to know if she was a carrier New baby son J How would she feel if she were a carrier? How would she feel about her new baby? Would it affect decisions about further

pregnancies?

XL Retinitis Pigmentosa

5

3

3

S

J

L

Testing children?

J has a 50% risk of being affected? Should he be tested? Would it affect parenting / schooling? Benefits to S – relieving uncertainty Benefits to J?

Meeting other family members

Individual needs / decisions Confidentiality Counselling issues evolve with time

Norrie’s disease

X-linked Blind at birth Additional risks

– 1/3 boys have learning difficulties– 1/3 boys develop deafness

Norrie disease

Chromosome 11p11.4NDP gene

Whole deletion inclNeighbouring MAO-A/B

Family

Tom

Shock It’s my fault How will I cope / my family

Sister about to start IVF treatment Burden of informing sister

Sister

50% chance she is carrier Able to offer a blood test Options

– Decide not to have a pregnancy– Continue with IVF (7/8 chance baby would

not have Norrie’s) or test a pregnancy– Have pre-implantation genetic diagnosis

Outcomes

Sister not a carrier, able to continue with IVF without anxiety

Tom doing extremely well. No learning difficulties or hearing problems. Very dedicated parents.

Future concerns that daughter could be a carrier. Will not offer testing until she can make her own choice.

Genetic testing for diagnosis:Can it be done?

Genes identified for wide range of retinal dystrophies are known

Genes able to besequenced

http://www.sph.uth.tmc.edu/Retnet/sum-dis.htm#D-graph

Molecular Genetic Testing

DNA sample (peripheral blood) Affected Individual / Obligate carrier

Identify sequence variant – not present in normal population

(monogenic disease) – In gene known to cause retinal disease

What is the Position in 2011?

Technological Advances mean tools

more powerful than ever

Many laboratories now offer diagnostic testing to the NHS

http://www.mangen.co.uk/molecular_eye_and_rare_disease.asp

Genetic testing for retinaldystrophies is possible and available

However testing is not universal

Where it is clearly required, testing is usually available

adRP

N = 1131

xlRP

n = 840

Why do patients require testing?Is the case for genetic testing persuasive?What is the evidence base?

Why develop genetic eye services?

Inequity of services Gene discovery Patient demand Treatment trials

Research to improve services

Regard study Programme Grant

Communication, accessibility Developing services for genetic

counselling and testing

Improving accessibility Hospital appointments by phone,

email Written information – large print,

email, braille, audio transcription Tactile genetic diagrams CCTV / software enlargement of

diagrams

Developing counselling services

Mainly anecdotal evidence of counselling needs of families with inherited eye disease

Requires robust research Evidence based MRC Framework for developing a

complex intervention

MRC framework

Phase 1– Modelling the intervention– Components

Phase 2– Exploratory trial

Randomised control trial

Aims

Design a patient led care model for counselling and testing

Develop evidence of patient benefit and “value” of improved counselling

Phase 1

“Modelling” Qualitative interviews with families and

healthcare professionals Snowballing Grounded theory

PPI Important to involve patients / users in design,

analysis and dissemination of research Regard Patient Advisory Group

– Patients / users / experts

– Leading charities (RNIB, BRPS, Guide Dogs, Macular Disease Society, NCBS, Genetic Alliance)

– Patients– VI researchers and social workers

PAG

Regular meetings Formal presentations (teaching, training, updates) Small group work

– Design methods Informal discussion Modify / improve design Regular email contact / updates and queries

– E.g. Review of patient information prior to Ethics application

– Publication of outputs included longer, more frequent meetings

Advantages of patient involvement

Motivation, extending knowledge base Relationships with pt support groups Focus work on improving patient care

– National patient perspective– Timely, fitting with patient needs

Collaboration– Genetic Alliance Route Maps, UK Vision strategy

workshop

Measuring benefit of genetic counselling

Outcome measuresInformation recall“satisfaction” surveyDepression / anxietyGenetic Empowerment scale

– Feelings around the condition, impact on family, hope for future, empowerment to make decisions

McAllister M et al, The Genetic Counseling Outcome Scale: a new patient-reported outcome measure for clinical genetics services Clinical Genet. 2011.

Phase 2

Exploratory trial– Feasibility of intervention– Pilot outcome measures / develop

estimates of effect size Economic “value”

– Willingness to pay– Economic modelling to understand cost

benefits of genetic testing

Conclusions

Retinal dystrophies important cause of VI in children/ young adults

Emotional need related to– VI– Family / genetic / treatment needs

Services patchily delivered Links to community support need to be

improved Research into delivery and impact required