from patient dna to personalized medicine · module coordinators: prof. dr. d.j.m. peters human...

Module coordinators:

Prof. dr. D.J.M. Peters

Human Genetics

[email protected]

Ph: 071 526 69490

From patient DNA

to personalized

medicine

Prof. dr. A.M.J.M. van den Maagdenberg

Human Genetics

[email protected]

Ph: 071 52 69460

M O D U L E B O O K

Bachelor Medicine, third year

Course year 2014-2015

Dr. W.M.C. van Roon-Mom

Human Genetics

[email protected]

Ph: 071 526 9435

© 2014 Alle rechten voorbehouden

LUMC

Behoudens de in of krachtens de Auteurswet van 1912 gestelde uitzonderingen, mag niets uit deze

uitgave worden verveelvoudigd en/of openbaar gemaakt worden door middel van druk, Photographkopie,

microfilm, web-publishing of op welke andere wijze dan ook en evenmin in een gegevensopzoeksysteem

worden opgeslagen zonder voorafgaande schriftelijke toestemming van de houder van de copyrights.

Voor vragen of informatie kunt u contact opnemen met:

Directoraat Onderwijs en Opleidingen, PB 9600, 2300 RC Leiden

Table of Contents

Module committee and teachers ............................................................................................................ 1

Overview involved teachers .................................................................................................................... 3

Overview programme ............................................................................................................................. 4

Preface ..................................................................................................................................................... 5

Introduction and general information .................................................................................................... 6

Study goals of the module ....................................................................................................................... 7

Competency lines .................................................................................................................................... 8

Assessment matrix .................................................................................................................................. 9

Assessment information ........................................................................................................................ 10

Theme 1: Monogenetic disorders: genetic testing & disease mechanisms ...................................... 13

Overview Programme Module Theme 1 ............................................................................................... 15

Theme 2: New Genome Analysis –Ethics ............................................................................................ 23


Theme 3: Gene(s) & environment ....................................................................................................... 26


Theme 4: Personal genomics: pharmacogenomics & genetic therapies ........................................... 44


Theme 5: Literature assignment: Writing report & Mini-symposium ............................................... 52


1

Modulecommitteeandteachers

Module coordinators

Prof. dr. D.J.M. Peters

Human Genetics

[email protected]

Prof. dr. A.M.J.M. van den Maagdenberg

Human Genetics

[email protected]

Dr. W.M.C. van Roon-

Mom

Human Genetics

[email protected]

Logistical support

[email protected]

Module committee

Dr. A.M. Aartsma-Rus

Human Genetics

Prof. dr. P. Devilee

Hukan Genetics

Prof. dr. H.J. Guchelaar

Clinical Pharmacology

Drs. A. van Haeringen

Clinical Genetics

Dr. P.A.C. ’t Hoen

Human Genetics

Prof. dr. P. de Knijff

Human Genetics

Dr. M. Kriek

Clinical Genetics

Dr. P.E.M. Taschner

Human Genetics

Prof. dr. ir. J.A.P. Willems van Dijk

Human Genetics

2

Secretariat

Mw. A.W. Remmelzwaal

Human Genetics

[email protected]

Involved disciplines:

Human Genetics (HG), Clinical Genetics (CG), Laboratory for Diagnostic Genome Analysis (LDGA), Cardiology (Car), Obstetrics (Obs), Neurology (Neur), Nephrology (Neph), Internal Medicine (IM), Gastroenterology (Gast), Medical Ethics (MedEth), Molecular Epidemiology (ME), Pathology (Path), Anatomy (Ana), Clinical Pharmacology (CP), Clinical Oncology (CO), Molecular Cell Biology (MCB), Medical Statistics (MedStat), Toxicogenetics (Tox), Endocrinology (Endo)

3

Overviewinvolvedteachers

Dr. M. Kriek (CG), Prof.dr. P. Devilee (HG), Drs. A. van Haeringen (CG),

Dr. R. Bökenkamp-Gramann (KJG), Prof.dr. M.H. Breuning (CG), Drs. S.

ten Broeke (CG), Dr. H.B. Ginjaar (LDGA), Prof.dr. M.J.T.H. Goumans

(MCB), Dr. N. Gruis (Huid), Dr. K.B.M. Hansson (LDGA), Dr. C. Harteveld

(LDGA), Drs. Y. Hilhorst-Hofstee (CG), Dr. N.S. den Hollander (CG), Dr.

M.R.M. Jongbloed (Ana) , Dr. S.G. Kant (CG), Dr. S.A.M.J. Lesnik

Oberstein (CG), Prof.dr. A.M.J.M. van den Maagdenberg (HG), Prof.dr. J.

Morreau (Path), Drs. M. Nielsen (CG), Prof.dr. D.J.M. Peters (HG), Dr.

W.M.C. van Roon-Mom (HG), Drs. D. Soonawala (Neph), Dr. C. Tops

(LDGA), Prof.dr. H.F.A. Vasen (Gast), Dr J.S. Verbeek (HG), Prof.dr.

J.J.G.M. Verschuuren (Neur)

Prof.dr. D.J.M. Peters (HG), Prof.dr. A.M.J.M. van den

Maagdenberg (HG), Dr. W.M.C. van Roon-Mom (HG),

Prof.dr. T. Hankemeier (UvL/LACDR), Prof.dr. S.M. van der

Maarel (HG), Prof.dr. G.J.B. van Ommen (HG)

Prof.dr. P. de Knijff (HG) and Dr. P.E.M. Taschner (HG),

Prof.dr. M.H. Breuning (CG), Dr. H.P.J. Buermans (HG),

Drs. J.N.G.M. van Dartel (MedEth), Prof.dr. J.T. den Dunnen (HG),

Mr. dr. R.E. van Hellemondt (MedEth), Dr. P.A.C. 't Hoen (HG),

Dr. M. Kriek (CG)Dr. G.W.E. Santen (CG), Dr. H. Sminia (HG),

Prof.dr. A. Tibben (CG)

Prof.dr. ir. J.A.P. Willems van Dijk (HG) and Dr. P.A.C. 't Hoen

(HG), Prof.dr. C.J. van Asperen (CG), Prof.dr. R. Fodde (Erasmus

MC), Dr. V.J.A. van Harmelen (HG), Dr. K.M. Hettne (HG), Prof.dr

J.J. van Hilten (Neuro), Prof.dr. A.M.J.M. van den Maagdenberg

(HG), Dr. E.C. Robanus Maandag (HG), Dr. M. Kriek (CG), Prof.dr.

H. Pijl (Endo), Dr. M. Roos (HG), Prof. dr. P. Slagboom (Epi), Dr.

G.M. Terwindt (Neuro), Dr. E.A. Tolner (HG), Dr. M.P.G.

Vreeswijk (HG), Dr. H. Vrieling (Tox), Dr. B. de Vries (HG)

Prof.dr. H.J. Guchelaar (CP) and Dr. A.M. Aartsma-Rus (HG), Dr. P. Bank (CP), Prof.dr. M.H. Breuning (CG), Prof.dr. A.J.

Gelderblom (CO), Dr. P.C. Giordano (CG), Dr. C.L. Harteveld (CG),

Dr. J. den Hartigh (CP), Dr. K. Janssen (CG), Prof.dr. J.-L. Kerkhof

(EUR), Dr. M. Lolkema (CO, UMCU), Dr. M. Phylipsen (CG), Dr. J.

Rens (Prosensa Therap.), Dr. J.J. Swen (CP), E. Vroom (DMD

Patient Association)

Week 1

Week 2

Monogenetic

disorders – genetic

testing in clinical

routine

New genome

analysis-

Ethics

Gene(s) and

environment

Personal genomics:

Pharmacogenetics

and genetic

therapies

Literature

assignment:

Writing report and

mini-symposium

Week 3

Week 4

Week 5

Week 6

Week 7

Week 8

Week 9

Week 10

4

Overviewprogramme

The students will write a research proposal and give an oral presentation. A

mini-symposium with keynote speakers will highlight the future of genetics

in the clinic.

Provide the students with a basic understanding of genetics in clinical

routine and learn how to establish a genetic diagnosis

Learning and discussing about the background and new opportunities

of next generation sequencing technologies, along with its ethical

implications

Identifying the opportunities and challenges of several genetic

therapies and the different perspectives of patients, clinicians and

industry on clinical trials. Through several case studies the influence of

the genome on response to drug treatment and the opportunity for

therapy development will be investigated.

Understanding the principles of complex diseases and the influence of

the environment. What is ‘risk prediction’ for complex diseases. A

clinical introduction of several diseases and functional studies in cell

and animal models of the respective diseases will be given.

Monogenetic

disorders – genetic

testing in clinical

routine

New genome

analysis-

Ethics

Gene(s) and

environment

Personal genomics:

Pharmacogenetics

and genetic

therapies

Literature

assignment:

Writing report and

mini-symposium

5

Preface

Today, we stand at the threshold of a new era in healthcare. Within the foreseeable future analysis

of a complete patient’s genome (e.g. full genome analysis) will play a prominent role in the

consulting rooms of almost every medical specialist. In other words, healthcare will become more

and more DNA-based.

Sequencing of the human genome was completed in 2001, providing a map of all genes at the base-

pair level. Above all, the complete sequence of the human genome has accelerated developments in

genetic testing technologies. Presently, all protein coding parts of the human genome can be

sequenced in just a few days at affordable costs. Genetic testing is therefore expected to change the

clinical routine for a broad range of diseases, beyond those with a clear familial background or

Mendelian inheritance pattern.

This Genomics revolution will have a fundamental impact on our healthcare system and this requires

different levels of basic knowledge of our genome for every healthcare professional. It is expected to

improve and accelerate the diagnosis, improve healthcare and facilitate a more personalized health

management, and raises the opportunity for the application of (new) targeted therapies. It is also

expected to create more detailed insight into the mechanisms of disease at the molecular, cellular

and organismal level. A possible downside would be e.g. ethical implications for patients and their

families

In this course, the student will learn how genetic testing will impact disease diagnosis, prognosis, and

treatment with examples from a broad range of medical disciplines. The student will get an

understanding of the basics of genetic testing in clinical routine and will learn how to establish a

genetic diagnosis. The student will be introduced into the concepts of Next Generation Sequencing

and the ethical concerns. It is important to understand the possibilities, but also the limitations of

large amounts of genomic data for clinical practice. Finally, the student will get a better

understanding of the implications for treatments, i.e. novel and cutting edge ideas for the

development of genetic therapies but also the influence of genetic variation on drug response so-

called Pharmacogenomics.

6

Introductionandgeneralinformation

7

Studygoalsofthemodule

Test form

Knowledge test/

Anamnesis

Knowledge test/ Grant proposal/Oral

presentation

Grant proposal/Oral

presentation

Knowledge test/

Gene to disease task

Knowledge test/ Grant proposal/Oral

presentation

Gene to disease task

Grant proposal/Oral

presentation

Learning objectives

The student can

take a family anamnesis and draw the patient pedigree

describe and explain the impact of the Next Generation

Sequencing (NGS) technologies in health care, as well as the

ethical consequences;

discuss how different clinical treatment strategies for different

clinical disciplines will be affected by implementation of NGS

will have a basic understanding of, and will be able to translate

the results of a genetic test into the clinic

understand and explain how the risk of patients for certain

diseases and/or their response to certain (pharmacological)

treatments can be affected by their genetic background

is able to describe the medical relevance of genomic variants

communicate acquired knowledge on genetics in the clinic in a

written report and oral presentation in a concise and structured

way

8

Competencylines

• Medical expert

• Scholar

• Collaborator and Manager

• Health advocate

Prerequisites

-Van Mens tot Cel (vakcode: 301117000Y);

-Van Cel tot Molecuul (vakcode: 301118000Y);

-Academische en Wetenschappelijke vorming (blok en lijn) (vakcode: 301119000Y).

Place in the curriculum

Year 3 (10 weeks; Level 300; points 15)

9

Assessmentmatrix

Assignment Gene to disease

task Anamnesis Knowledge

test Grant proposal Oral

Presentation

Type of exam

Computer assignment

Written exam Written exam

Report of 1000 words + 2 illustrations

(end assignment)

Oral Presentation (end assignment)

Area Knowledge, academic skills

Knowledge, professional skills

Knowledge, academic skills, global health

Academic skills, knowledge, global health, communication, collaboration

Academic skills, communication, collaboration

Time Week 5 Week 5 Week 9

Week 9-10 Week 9-10

Lenght

1 hour 1 hour 1 hour 30 hour preparation

10 hour preparation

Weight

(% of end mark)

10% 10 % 25 %

40 %

15 %

Collaboration Individual basis Individual basis Individual basis

In pairs In pairs

Assessed by

Minor teachers

Medical Specialists involved in the half minor

Minor teachers

Minor teachers Assigned tutor plus minor teachers

Number of questions

4 8 20 Not applicable Not applicable

10

Assessmentinformation

Week 5:

Gene to disease task:

Computer assignment. The knowledge obtained in computer tasks in week 1-6 will be tested. The

exam exists of 4 open questions

Rating: 1-10

Assessed by: 2 minor teachers

Assessment: Application of bioinformatics skills to a clinical problem.

Feedback: By course coordinators in week 8

Week 6:

Anamnesis

The knowledge to establish a genetic anamnesis obtained in weeks 1-5 will be tested in a multiple

choice test.

Rating: 1-10

Assessed by: 2 minor teachers (clinical background)

Assessment: Application of clinical skills to reach a clinical genetic diagnosis

Feedback: By the assessment minor teachers

Week 9:

Knowledge test

Final multiple choice exam testing the students’ knowledge on genetic technologies, monogenetic

disorders, genetic testing in a clinical routine, genes and environment, pharmacogenetics, genetic

therapies and ethics.

Rating: 1-10

Assessed by: Course coordinators

Assessment: Application of genetics knowledge to genetic technologies, monogenetic disorders,

genetic testing in a clinical routine, genes and environment, pharmacogenetics, genetic therapies and

ethics.

Week 10

Grant proposal

Write a project proposal of 1500-2000 words in groups of two students.

Rating: 1-10

Assessed by: course coordinators expert researcher that supervised the students during their

assignment

Assessment: The written report will be graded with respect to scientific accuracy, quality of the

experimental part of the proposal, and how well it reflects the combination of knowledge on several

criteria that will be explained to the student when the proposal tasks are handed out (October 27

9.00 – 10.00). The individual contribution of each student to the preparation of the written proposal

will be assessed by the minor teachers involved in the specific subject of the proposal and by the

course coordinators. The three course organizers will compare the reviews of the expert researchers

11

and give final marks for the written assignment. Each student will get an individual mark. Students

will receive their final mark within 3 weeks after the end of the course.

Feedback: Students will get a short written feedback by the expert researcher through email.

Week 10:

Oral presentation of topic related to the project proposal:

Give a power point presentation on a particular subject in groups of two students.

Rating: 1-10

Assessed by: course coordinators and expert researchers

Assessment: Each student will get an individual mark. Students will receive their final mark within 3

weeks after the end of the course. Together with the expert researchers that supervised the student

group in the final two weeks, the course organisers will judge whether students will be graded either

half a point higher or lower than the group average for the oral presentation or whether the student

will get the mark of the group presentation. This allows for a differentiation in the evaluation in case

the students performed differently well during the group assignment.

Feedback: Students will get feedback during the presentations.

Study books

Emery’s Elements of Medical Genetics, by P. Turnpenny, S. Ellard

Relevant websites

http://www.ncbi.nlm.nih.gov/omim

http://www.lgtc.nl/

http://genome.ucsc.edu/

http://www.ncbi.nlm.nih.gov/SNP/

13

Theme1:

Monogeneticdisorders:genetictesting&diseasemechanisms

Clinical and Scientific

coordinators: Dr. M. Kriek (CG) and Prof.dr. P. Devilee (HG), Drs. A. van Haeringen (CG)

Other teachers involved: Dr. R. Bökenkamp-Gramann (KJG), Prof.dr. M.H. Breuning (CG), Drs. S.

ten Broeke (CG), Dr. H.B. Ginjaar (LDGA), Prof.dr. M.J.T.H. Goumans

(MCB), Dr. N. Gruis (Huid), Dr. K.B.M. Hansson (LDGA), Dr. C. Harteveld

(LDGA), Drs. Y. Hilhorst-Hofstee (CG), Dr. N.S. den Hollander (CG), Dr.

M.R.M. Jongbloed (Ana) , Dr. S.G. Kant (CG), Dr. S.A.M.J. Lesnik

Oberstein (CG), Prof.dr. A.M.J.M. van den Maagdenberg (HG), Prof.dr. J.

Morreau (Path), Drs. M. Nielsen (CG), Prof.dr. D.J.M. Peters (HG), Dr.

W.M.C. van Roon-Mom (HG), Drs. D. Soonawala (Neph), Dr. C. Tops

(LDGA), Prof.dr. H.F.A. Vasen (Gast), Dr J.S. Verbeek (HG), Prof.dr.

J.J.G.M. Verschuuren (Neur)

In the first two weeks of this course, we will discuss the present-day clinical routine for a number of

medical disciplines, including Neurology, Cardiology, Oncology, Nephrology, and Gastroenterology.

What is the anamnesis of an ‘average patient’ seen in these clinics, and how often is a genetic

diagnosis warranted? How is this differential diagnosis established and which diagnostic information

is essential to arrive at the right diagnosis? This will be exemplified by patient demonstrations. In

addition, this part of the course will refresh basic genetic principles, such as inheritance patterns,

chromosomal disorders, and diagnostic approaches.

Learning objectives:

The student

• will be able to establish if and when a genetic diagnosis in the clinical arena is warranted for

optimal treatment of the patient.

• can take a family anamnesis and draw the patient pedigree.

• will be able to draw diagnostic conclusions on the most likely genetic cause of a patient’s

disease on the basis of his/her personal anamnesis and family history.

• can discuss the genetic, disease-related and anamnestic complexities of a variety of disorders

for which heritability forms an important part of their etiology.

• can explain the differences between various inheritance patterns, including monogenic

versus polygenic inheritance.

• will acquire and apply knowledge on chromosomes, genes, and variation in DNA sequences.

• will have a basic understanding of, and will be able to translate the results of a genetic test

into the clinic.

• will be able to describe the clinical implications of a genetic diagnosis to counselees for

several clinical disciplines.

This part of the course will include:

- Genetic diseases in daily practice: lectures and patient demonstrations for different disorders,

i.e. colon cancer, developmental, neuromuscular, cardiac and renal disorders

- Lectures and practical skills in genetic counselling

- Lectures, working group and quiz on monogenetic inheritance patterns and conventional

genome analysis

- An interactive lecture and debate on prenatal screening

- From mice to man: animal models to study monogenetic diseases

14

- In depth approach of a clinical problem: critical evaluation of literature to answer a question

from clinical practice – Self-study, working group and presentations

Contact hours 22: e.g. lectures, patient demonstrations

Interaction hours 15: e.g. practicals, contact hours, quiz

Self-study hours 14

Evaluation:

-10 minute student presentation

- Multiple choice exam

- Quiz

Knowledge that the Student should have prior to entering the Minor:

Chapters 2-5, 7, 16-22 Emery’s Elements of Medical Genetics, by P. Turnpenny, S. Ellard

15

OverviewProgrammeModuleTheme1

Topic Type of activity Name

Week 1 Monday September 1

Tuesday September 2 Conventional genome analysis

9.00-9.30 Introduction - 1/2 Minor Lecture Prof.dr. A. van den Maagdenberg, Prof.dr. D.H.M. Peters and Dr. W.M.C. van Roon-Mom

9.30-9.45 Introduction first two weeks Lecture Prof.dr. P. Devilee and Dr. M. Kriek

10.00-10.45 Genetic Counseling Lecture Prof.dr. M.H. Breuning

11.00-11.45 Chromosomes/DNA/genes- the complexity of the genome Lecture Dr. M. Kriek

13.00-13.45 Monogenic inheritance- different types, case-based explanation Quiz Dr. M. Kriek

14.00-14.45 Genetic Linkage Lecture Dr. N. Gruis

15.00-15.45 Patient demonstration- Malformation -Myotonic dystrophia Patient demonstration Drs. A. van Haeringen

Wednesday September 3

9.00-9.45 Patient demonstration developmental delay - Williams syndrome Patient demonstration Drs. A. van Haeringen

10.00-10.45 Prenatal diagnostics in daily clinical genetic practice Lecture Dr. N.S. den Hollander

11.00-11.45 NIPT heelprick discussion Lecture Prof.dr. M.H. Breuning

13.00-13.45 Background of in depth approach of a clinical problem Contact Drs. A. van Haeringen and Dr. M. Kriek

14.00-14.45 Assignment Question/answer approach Contact Drs. A. van Haeringen and Dr. M. Kriek

15.00-16.45 Assignment Question/answer approach Self study

Thursday September 4 Developmental aberrations

9.00-9.45 Chromosome analysis Lecture Dr. K.B.M. Hansson and Dr. C. Harteveld

10.00-10.45 SNP array analysis Lecture Dr. K.B.M. Hansson and Dr. C. Harteveld

11.00-11.45 Mutation scanning Lecture Dr. K.B.M. Hansson and Dr. C. Harteveld

13.00-14.45 Interpretation of sequence data using Alamut Practical Dr. C. Tops

15.00-16.45 Interpretation of sequence data using Alamut Practical Dr. C. Tops

Friday September 5

9.00-10.15 Discussion of outcome of assignment. Contact Drs. A. van Haeringen and Dr. M. Kriek

10.30-11.15 neurology in daily practice Lecture Prof. dr. J.J.G.M. Verschuuren

11.30-12.15 CADASIL Lecture Dr. S.A.M.J. Lesnik Oberstein


Week 2 Monday September 8 Lecture

9.00-9.45 Cardiology/ Daily practice Lecture Dr. R. Bökenkamp-Gramann

9.45-10.30 Link between Clinical Genetics and cardiology Lecture Dr. Y. Hilhorst

10.30-11.00 pauze

11.00-11.45 Morphogenesis and anatomy of congenital heart disease Lecture Dr. M.R.M. Jongbloed

11.45-12.30 Stem cell therepy in cardiac disease: from cells to patient therapy Lecture Prof. dr. M.J.T.H. Goumans

14.00-16.45 In depth approach of a clinical problem self study

Tuesday September 9

9.00-9.45 Gastro-intestinal hepatologist: patients in daily practice Lecture Prof.Dr. H.F.A. Vasen

10.00-10.45 Heriditary forms of Colon cancer: clinical genetics Monogenetic Lecture Dr. M. Nielsen

11.00-12.15 Microscopy of heriditary colon cancer samples Practical Prof. dr. J. Morreau

13.00-13.30 Scientific research in colon cancer Lecture Drs. S. ten Broeke

13.30-14.30 In depth approach of a clinical problem, contact with senior contact/self study Drs A. van Haeringen, dr. M. Kriek and Prof.dr. Devilee



9.00-9.45 Mouse models to study genetic diseases Lecture Dr. J.S. Verbeek

10.00-10.45 Nephrologist:patients in daily practice patient demonstration Drs. D. Soonawala

11.00-12.00 Polycystic Kidney Disease: from mice to patients Lecture Prof. dr. D.J.M. Peters

13.00-13.45 Limb Girdle Muscular Dystrophy: genotype-phenotype Lecture Dr. H.B. Ginjaar


Thursday September 11

9.00-9.45 Counseling session by students, of students about a disorder practical Drs van Haeringen and Dr. M. Kriek

10.00-10.45 Pedigree drawing/ physical examination /ordering DNA test etc by students practical Drs van Haeringen and Dr. M. Kriek

11.00-11.45 Patient demonstration: kleingroei (Acromesomele dysplasie) practical/patient demonstration Dr. S.G. Kant


Friday September 12

9.00-12.30 In depth approach of a clinical problem - presentation by students Assessment Drs A. van Haeringen, dr. M. Kriek and Prof.dr. Devilee

16

Tuesday September 2

Lecture 9.00 – 09.30

Title Introduction to this half minor

Instructors: Prof.dr. A. van den Maagdenberg, Prof.dr. D.H.M. Peters and Dr. W.M.C. van Roon-

Mom

Goal Introductory remarks

Lecture 9.30 - 9.45

Title Introduction first two weeks

Instructors Prof.dr. P. Devilee and Dr. M. Kriek

Goal Explaining the specific goals and learning targets for the first two weeks of the

course.

Lecture 10.00-10.45

Title Genetic Counselling

Instructor Prof.dr. M.H. Breuning

Goal To understand the process of genetic counselling and its clinical ramifications.

Genetic counselling is the process by which patients or relatives at risk of an

inherited disorder are advised of the consequences and nature of the disorder, the

probability of developing or transmitting it, and the options open to them in

management and family planning. This complex process can be separated into

diagnostic (the actual estimation of risk) and supportive aspects. An important part

of the counselling’s process are the relevant anamnestic questions to ask. In this

lecture, and in others, these relevant questions will continue to be discussed.

Lecture 11.00-11.45

Title Chromosomes/DNA/genes - the complexity of the genome

Instructor Dr. M. Kriek

Goal To understand the basis of how genes and genetic materials are organized in

humans. In modern molecular biology and genetics, the genome is the genetic

material of an organism. It is encoded either in DNA or, for many types of viruses, in

RNA. The genome includes both the genes and the non-coding sequences of the

DNA/RNA.

Quiz 13.00-13.45

Title Monogenic inheritance- different types, case-based explanation


Goal To refresh knowledge – in a question-and-answer-session – on monogenetic

Mendelian inheritance, i.e., autosomal or sex-linked inheritance, dominant or

recessive inheritance.

Lecture 14.00-14.45

Title Genetic Linkage

Instructor Dr. N. Gruis

Goal To understand the basic principles underlying Mendelian inheritance, and genetic

linkage. Genetic linkage is the tendency of genes that are located proximal to each

other on a chromosome to be inherited together during meiosis. Genes whose loci

are nearer to each other are less likely to be separated onto different chromatids

during chromosomal crossover, and are therefore said to be genetically linked.

Patient demonstration 15.00-15.45

17

Title Malformation -Myotonic dystrophia

Instructor Drs. A. van Haeringen

Goal Gain experience with different aspects of a genetic counselling and learn what the

implication are of a DNA verified diagnosis for the patient and his/her family. In this

patient demonstration the emphasis will be on how one patient can lead to an

extensive family with multiple affected family members. Again, relevant anamnestic

questions will show to be very important in this process.

Wednesday September 3 -

Patient Demonstration 9.00-9.45

Title Patient demonstration developmental delay – Williams Syndrome –

Instructor Drs A. van Haeringen


implications are of a DNA verified diagnosis for the patient and his/her family. In this

patient demonstration the emphasis will be on the impact of getting a genetic

diagnosis in a child, and what the impact is on daily life at home and at school.

Lecture 10.00-10.45

Title Prenatal diagnostics in daily clinical genetic practice

Instructor Dr. N.S. den Hollander

Goal To understand which prenatal questions are addressed in clinical genetic practice.

Some pregnancies have an increased chance of genetic disorder / chromosome

alteration. Examples of these situations are:

• Previous child with a genetic disorder/syndrome

• Fetus with an increased nuchal translucency

• Fetus with structural abnormalities observed during the 20 weeks ultrasound

During this lecture the students will get an inside of the different prenatal issues that

are discussed with the pregnant women and their partners.

Interactive Lecture 11.00-11.45

Title NIPT Heel prick discussion

Instructor Prof.dr. M.H. Breuning

Goal Introduction of the heel prick and its related social discussions. The neonatal heel

prick or Guthrie test is a screening test done on newborns. Currently the newborn is

screened for the genetic predisposition of ~25 disorders. These disorders are

medically actionable in the sense that there is an opportunity to prevent a problems

by direct clinical intervention. The question is whether it is appropriate to expand the

application of the heel prick by also including disorder that are not medically

actionable for the newborn, but could have direct consequences for the family

involved.

Contact 13.00-13.45

Title Background of in-depth approach of a clinical problem

Instructors Drs. A. van Haeringen and Dr. M. Kriek

Goal During this session students are taught how to access an in-depth approach of a

clinical problem by discussing an already completed approach.

Contact 14.00-14.45

Title Assignment Question/answer approach

18


Goal Gain experience with the in-depth approach by studying a rather simple clinical

problem. This problem will initially be similar for all students so that possible

obstacles can be identified plenary.

Self-study 15.00-16.45

Goal Gain experience with the in-depth approach by self-study.


Lecture 9.00-9.45

Title Chromosome analysis

Instructors Dr. K.B.M. Hansson and Dr. C. Harteveld

Goal To learn about different applications of chromosome analysis or karyotyping.

Karyotyping is a test that evaluates the number and structure of a person's

chromosomes in order to detect abnormalities. Chromosomes are thread-like

structures within each cell nucleus and contain the body's genetic blueprint. Each

chromosome contains hundreds of genes in specific locations. These genes are

responsible for a person’s inherited physical characteristics and they have a profound

impact on growth, development, and function.

Lecture 10.00-10.45

Title SNP array analysis


Goal To understand why Single nucleotide polymorphism (SNP) array has a significant

added value compared to karyotyping in a diagnostic setting. SNP array can be used

to measure both DNA polymorphism and dosage changes. Our laboratory has applied

SNP microarray analysis to uncover sub-microscopic genomic copy number gains and

losses in different cancers. This session will focus on the range of applications of SNP

microarray analysis.

Lecture 11.00-11.45

Title Mutation scanning


Goal To learn about different applications of mutation scanning, a process by which a

segment of DNA is screened via one of a variety of methods to identify variant gene

region(s). Variant regions are further analyzed (usually by sequence analysis or

mutation analysis) to identify the sequence alteration.

Practical 13.00-14.45 & 15.00 – 16:45

Title Interpretation of sequence data using Alamut

Instructor Dr. C. Tops

Goal Gain experience with software that is used in a diagnostic setting to support the

decision making process. Alamut Visual integrates genetic and genomic information

from different sources into one consistent and convenient environment to describe

variants using HGVS nomenclature and help interpret their pathogenic status.

Dedicated to mutation diagnostics, Alamut Visual is used by clinical and molecular

research laboratories worldwide.

19

Friday September 5

Contact 9.00-10.15

Title Discussion of outcome of assignment


Goal Feedback of the first assignment and identification of possible obstacles that should

be addressed prior to the start of a real in-depth approach of a clinical problem.

Lecture 10.30-11.15

Title (Child) neurologist; neurology in daily practice

Instructor Prof. Dr. J.J.G.M. Verschuuren

Goal To learn about the variety of clinical issues addressed in daily practice of a

neurologist (specialized in neuromuscular disorders). Disorders discussed will be

Duchenne and Becker muscular dystrophy, Facio- Humeral- Scapulo Dystrophy

(FSHD) en Limb Girdle Muscular Dystrophy (LGMD).

Lecture 11.30-12.15

Title CADASIL

Instructor Dr. S.A.M.J. Lesnik Oberstein

Goal To understand the clinical and genetic issues related to CADASIL (Cerebral autosomal

dominant arteriopathy with subcortical infarcts and leukencephalopathy). The

students will gain insight into the importance of a multidisciplinary approach of the

(pre-symptomatic) counselling process.

Monday September 8

Lecture 9.00-9.45

Title Cardiology – Daily practice

Instructor Dr. R. Bökenkamp-Gramann


cardiologist. Cardiology includes medical diagnosis and treatment of congenital heart

defects, coronary artery disease, heart failure, valvular heart disease and

electrophysiology.

Lecture 9.45-10.30

Title Link between Clinical Genetics and cardiology

Instructor Dr. Y. Hilhorst-Hofstee

Goal: Gain insight into the proportion of cardiac problems that are part of a genetic disorder /

syndrome; how are the patients identified, what is the expertise of the clinical geneticist.

Lecture 11.00-11.45

Title Morphogenesis and anatomy of congenital heart disease

Instructor Dr. M.R.M. Jongbloed

Goal To understand how structural heart abnormalities are diagnosed in a clinical setting.

Lecture 11.45-12.30

Title Stem cell therapy in cardiac disease – from cells to patient therapy

Instructor Prof.dr. M.J.T.H. Goumans

20

Goal To understand different levels of scientific research related to cardiac disease.


Title In-depth approach of a clinical problem

Goal Formulating an answer to a clinical problem by an in-depth literature study

approach.

Tuesday September 9

Lecture 9.00-9.45;

Title Gastro-intestinal hepatologist: patients in daily practice

Instructors Prof.dr. H.F.A. Vasen


gastroenterologist. Gastroenterology and Hepatology specialists provide

comprehensive clinical services related to the digestive tract, liver and pancreas.

They diagnose and manage complex and chronic gastrointestinal and liver disorders.

Lecture 10.00-10.45

Title Hereditary forms of Colon cancer – clinical genetics Monogenetic

Instructor Dr. M. Nielsen

Goal Gain insight of the proportion of intestinal problems that are part of a genetic

disorder / syndrome; how are the patients identified, what is the expertise of the

clinical geneticist.

Practical 11.00-12.15

Title Microscopy of hereditary colon cancer samples

Instructor Prof.dr. J. Morreau

Goal To understand the process of diagnostic process related to hereditary colon cancer

on a histological level.

Lecture 13.00-13.30

Title Scientific research in colon cancer

Instructor Drs. S. ten Broeke

Goal To understand how scientific research is set up. Drs. ten Broeke will discuss data

assembly, analysis of families with hereditary colon cancer related disorder and

estimated penetrance of the different disorders.

Contact/ Self-study 13.30-14.30

Title In-depth approach of a clinical problem, contact with senior

Instructor Drs A. van Haeringen, dr. M. Kriek and Prof.dr. Devilee

Goal To address questions related to the in-depth approach

Self-study 14.30-16.00;


21

Goal Formulating an answer to a clinical problem by an in-depth literature study approach


Lecture 9.00-9.45

Title Mouse models to study genetic diseases

Instructor Dr J.S. Verbeek

Goal To understand the possibilities of the application of animal model to study a genetic

disorder. An animal model is a living, non-human animal used during the research

and investigation of human disease, for the purpose of better understanding the

disease process without the added risk of harming an actual human. The animal

chosen will usually meet a determined taxonomic equivalency to humans, so as to

react to disease or its treatment in a way that resembles human physiology as

needed. Many drugs, treatments and cures for human diseases have been developed

with the use of animal models. Predictive models are similar to a particular human

disease in only a couple of aspects. However, these are useful in isolating and making

predictions about mechanisms of a set of disease features.

Practical 10.00-10.45;

Title Nephrologist – patients in daily practice

Instructors Drs. D. Soonawala


Nephrologist. Nephrology concerns itself with the study of normal kidney function,

kidney problems, the treatment of kidney problems and renal replacement therapy

(dialysis and kidney transplantation).

A patient with Polycystic kidney disease(PKD) will be interviewed. PKD is one of the

most common life-threatening genetic diseases, affecting an estimated 12.5 million

people worldwide. It is a cystic genetic disorder and is characterized by the presence

of multiple cysts (hence, "polycystic") typically in both kidneys. The two major forms

of polycystic kidney disease are distinguished by their patterns of inheritance.

Lecture 11.00-12.00

Title Polycystic Kidney Disease – from mice to patients

Instructor Prof.dr. D.J.M. Peters

Goal To understand different levels of scientific research related to Polycystic kidney

disease, with focus on model systems.

Lecture 13.00-13.45

Title Limb Girdle Muscular Dystrophy – from genotype to phenotype

Instructor Dr. H.B. Ginjaar

Goal To understand the diagnostic approaches for molecular verification (or exclusion) of

a clinical muscular diagnosis. Limb-girdle muscular dystrophy is an autosomal class of

muscular dystrophy that is similar but distinct from Duchenne muscular dystrophy

and Becker's muscular dystrophy. Limb-girdle muscular dystrophy encompasses a

large number of rare disorders.

22

Self-study 14.00-16.45;




Practical 09.00-09.45;

Title Counseling session by students, of students about a disorder

Instructors Drs van Haeringen and Dr. M. Kriek

Goal Gain experience with counseling. Which questions should be asked to identify a

possible genetic cause of a certain phenotype.

Practical 10.00-10.45

Title Pedigree drawing/ physical examination /ordering DNA test etc by students


Goal Gain experience with pedigree drawing, physical examination and sequent ordering

different DNA tests.

Patient demonstration 11.00 – 11.45;

Title Kleingroei (Acromesomele dysplasie)

Instructor Dr. S.G. Kant


implications are of a DNA verified diagnosis for the patient and his/her family.




Friday September 12

Contact 09.00 – 12.30; presentations, discussion, assessment

Title In-depth approach of a clinical problem – presentation by students

Instructors Drs A. van Haeringen, dr. M. Kriek and Prof.dr. Devilee

Goal During this session, the students will give a presentation in which they answer the

clinical problem that was addressed during the last days by applying an in-depth

literature study.

23

Theme2:NewGenomeAnalysis–Ethics


coordinators: Prof.dr. P. de Knijff (HG) and Dr. P.E.M. Taschner (HG)

Other teachers involved: Prof.dr. M.H. Breuning (CG), Dr. H.P.J. Buermans (HG), Drs. J.N.G.M. van

Dartel (MedEth), Prof.dr. J.T. den Dunnen (HG), Mr. dr. R.E. van

Hellemondt (MedEth), Dr. P.A.C. 't Hoen (HG), Dr. M. Kriek (CG)Dr.

G.W.E. Santen (CG), Dr. H. Sminia (HG), Prof.dr. A. Tibben (CG)

In recent years, the application of "Next generation sequencing” ( NGS ) really has taken off in

medical research and diagnostics . The major difference to conventional method is that millions of

reactions can be analyzed in parallel, in contrast to only one fragment in conventional sequencing.

This has major advantages but also raises ethical questions related to unexpected information

concerning possible diseases.

In week 3 and 4 the principle of NGS and its applications will be discussed as well as ethical

questions. NGS, and especially exome sequencing has identified many causative genes for hereditary

and congenital disorders in recent years. Using examples, it is illustrated why NGS is suitable for this

purpose and some of the problems that are encountered. The application of NGS as a diagnostic tool

will also be discussed. The impact on health in a broader sense is also prominent. It is very likely that

genome-wide analysis will play a prominent role in many doctor's offices and throughout all levels of

health care in the near future. Here, it is important to know what information the

student can, and cannot (yet) get out of the genome. It is currently impossible, for example, to

generate a reliable genetic risk profile. There is also a risk of chance findings. This means that a

genetic modification is identified that has no relation with the condition of the patient, but could

have clinical consequence. Patients should be informed well in advance of this possibility.


The student

• will be able to describe next-generation sequencing in terms of technology, different

types of data analysis, and applications

• can assess the potential consequences of a DNA variant

• can discriminate between genetic and non-genetic phenotypes

• can describe the complexity of the content of a personal genome

• can discuss the various ethical, philosophical and legal aspects and implications of the

rapid changes in medical research.

• will be able to systematically analyse the moral implications of clinical counselling

• can discuss the moral and legal conditions of a genetic population survey

• can name the different responsibilities and organizations important in the field of

genetic screening and population surveys.


- Implications of genomic medicine based on the concept of everyday medical practice. Current

transformation of medicine: from cure to improvement. Developments in the future: from

enhancement to trans-humanism?

- Clinical genetics: which ethical and legal questions arise in clinical (counseling) practice? Related

Topics: secrecy and privacy; shifting family relationships

- Genetic screening and screening. Related topics: government role, role provider. Protection,

autonomy and self-management support. Equitable access.

24

- Direct-to-consumer genetic testing. Related topics: government role, role provider. Protection,

autonomy and self-management support. Equitable access.

Contact hours 24: including lectures and patient demonstrations

Interaction hours 14: including practicals, quiz, presentations

Self-study hours 12

Evaluation:

- Presentation of a clinical problem


Chapters 4, 17, 20, 24 Emery’s Elements of Medical Genetics, by P. Turnpenny, S. Ellard

25




9.00-9.15 Introduction Contact Coordinators

9.15-10.00 NGS technology: history and current Lecture Prof.dr. J.T. den Dunnen

10.15-11.00 NGS technology: current and future Lecture Prof.dr. J.T. den Dunnen

11.15-12.15 Task data analysis (exome based) Practical Dr. H. Sminia

12.15-12.30 Saliva sampling for DNA analysis Practical Dr. H.P.J. Buermans

13.00-16.30 Self study assignment: Knowledge from fictitious genome Self study

16.30-17.30 Reading review and preparing questions Self study

Tuesday September 16

9.00-9.45 NGS data analysis: Types of variants Lecture Dr. P.E.M. Taschner

10.00-10.45 NGS data analysis: Potential consequences of a variant Lecture Dr. P.E.M. Taschner

11.00-11.45 WES/WGS and data analysis Lecture Dr. G.W.E. Santen

12.00-12.30 Databases and Genome browsing Practical Dr. P.E.M. Taschner

13.00-17.00 Prepare presentation September 24 - Knowledge from genome Self study


9.00-11.00 Is this heritable or not Q&A voting Prof. dr. P. de Knijff

I have a genome, what do I know Q&A > task for studentsProf. dr. P. de Knijff

11.15-12.30 Databases and Genome browsing Practical Dr. H. Sminia

13.00-17.00 Prepare presentation September 24 - Knowledge from genome Self study


9.00-9.45 Ethics and law: Implications of Genome based Medicine Lecture Dr. J.N.G.M. van Dartel and Mr. dr. R.E. van Hellemondt

10.00-12.30 Transhumanism and other images of the future Working group Dr. J.N.G.M. van Dartel and Mr. dr. R.E. van Hellemondt

13.00-17.00 Ethics self-study and tasks Self study

Friday September 19

9.00-9.45 Practical and emotional implications of a severe genetic diseasePatient demonstration Prof.dr. A. Tibben

9.45-12.30 Family Dynamics Lectures Prof.dr. A. Tibben, Dr. J.N.G.M. van Dartel, Mr. dr. R.E. van Hellemondt

13.00-17.00 Ethics selfstudy and tasks Self study



9.00-10.00 DNA isolation Practical Dr. H.P.J. Buermans

10.00-11.00 LGTC/Sequencing facility tour Dr. H.P.J. Buermans

11.00-12.00 DNA quantification Practical Dr. H.P.J. Buermans

13.00-14.00 Prepare for practicals and presentation Self study

14.00-15.00 PCR setup for DNA profile & SNV test Practical Dr. H.P.J. Buermans


9.00-9.45 Transcriptomics, proteomics, metabolomics Lectures Dr. P.A.C. 't Hoen

10.00-10.45 The future hospital, personal monitoring Lectures Prof.dr. M.H. Breuning

11.00-11.45 My genome sequence Q&A what do I know Dr. M. Kriek

13.00-16.00 DNA profile & SNV test Practical Dr. H.P.J. Buermans


13.30-17.00 Presentations knowledge from your genome 10 min students presentationsProf. dr. P. de Knijff, Dr. H. Sminia


9.00-12.15 Ethics and Law: Incidental findings Lectures Dr. M. Kriek, Mr. dr. R.E. van Hellemondt and Dr. J.N.G.M. van Dartel

13.00-17.00 Ethics and Law: The future of neonatal screening Practical Dr. M. Kriek, Mr. dr. R.E. van Hellemondt and Dr. J.N.G.M. van Dartel

Friday September 26

9.00-16.00 Ethics and law: Commercial screening Lectures Dr. M. Kriek, Mr. dr. R.E. van Hellemondt and Dr. J.N.G.M. van Dartel

16.00-17.00 Evaluation with students Contact Dr. M. Kriek and Dr. J.N.G.M. van Dartel

26

Theme week 3 & 4: New Genome Analysis – Ethics

Monday September 15

Contact 9.00 – 9.15

Title Evaluation with students

Instructors Coordinators

Goal Evaluation.

Lectures 9.15 – 10.00; 10.15 – 11.00

Title NGS technology: 1) history and current; 2) current and future

Instructor Prof. Dr. J.T. den Dunnen (Head Leiden Genome Technology Center (LGTC); Human

Genetics department, LUMC)

Goal Next Generation Sequencing technology has great impact on research and DNA

diagnostics. Students will receive a short introduction on NGS technology.

Practical 11.15 – 12.15

Title Task data analysis (exome based)

Instructor Dr. H. Sminia (Human Genetics department, LUMC)

Goal Students get their fictitious genome. This genome is a random selection of variants

from the 1000 genomes project. This genome is stored in a gene variant database

and has been enriched with variants that will be used during this minor to

demonstrate the relation between gene variants and phenotype. The students will

learn how to look for information in their genome in order to fulfil their assignments.

Practical 12.15 – 12.30

Title Saliva sampling for DNA analysis

Instructor Dr. H.P.J. Buermans (LGTC, Human Genetics department, LUMC)

Goal Students will provide saliva samples to isolate their own DNA for use in later

practicals.

Self-study 13.00 – 16.30

Title Knowledge from fictitious genome

Goal Students will read background information to prepare for their data analysis tasks.

The assignment is to search their genomes for variants linked to severe genetic

disorders and other variants that are associated with interesting phenotypes or

traits. Students will use their results to prepare their presentations for Wednesday

September 24 - Knowledge from genome according to the following guidelines:

1. Prepare a presentation of 10-15 min and include appropriate images

2. Explain the application of genome analysis

3. Explain the principle of genome analysis

4. Show a typical result from genome analysis

27

5. Explain how these results should be interpreted

Self-study 16.30 – 17.30

Title Reading review and preparing questions for lecture Tuesday September 16 Dr.

G.W.E. Santen (11.00 – 11.45)

Goal Each student has to prepare a question for the lecture based on the article below

Literature de Ligt et al. Diagnostic Exome Sequencing in Persons with Severe Intellectual

Disability. N Engl J Med 2012;367:1921-9.


Lectures 9.00 – 9.45; 10.00 – 10.45

Title 1) NGS data analysis, types of variants; 2) Potential consequences of a variant

Instructor Dr. P.E.M. Taschner (Human Genetics department, LUMC)

Goal Students will learn which types of variants can be detected and what their potential

consequences on gene function can be.

Lecture 11.00 – 11.45

Title WES/WGS and data analysis

Instructor Dr. G.W.E. Santen (Clinical Genetics department, LUMC)

Goal Whole exome (WES) and genome (WGS) sequencing techniques are rapidly being

introduced in clinical diagnostics. With WES and especially WGS many variants are

identified, and finding the causative variant(s) in a patient is not always

straightforward. The relative merits of WES and WGS will be discussed, and the

difficulties in the analysis of this type of large datasets will be illustrated using

several examples.

Practical 12.00 – 12.30

Title Databases and Genome browsing

Instructor Dr. P.E.M. Taschner (Human Genetics department, LUMC)

Goal Students will learn to find information needed to fulfil their exome-based data

analysis tasks and prepare their presentations.

Self-study 13.00 – 17.00

Title Knowledge from genome

Students continue to prepare their presentations for Wednesday September 24 -

Knowledge from genome.

28


Q&A voting 9.00 – 11.00

Title 1) Is this heritable or not? 2) I have a genome, what do I know?

Instructor Prof. dr. P. de Knijff (FLDO, Human Genetics department, LUMC)

Goal During this mix of lecturing and Q&A, students will be familiarized with the

consequences of knowing genome variation based health predictions using

aconcrete and detailed case example.

Practical 11.15 – 12.30

Title Databases and Genome browsing

Instructor Dr. H. Sminia (Human Genetics department, LUMC)

Goal Students will learn to find information needed to fulfil their exome-based data

analysis tasks and prepare their presentations.

Self-study 13.00 – 17.00





Lecture 9.00 – 9.45

Title Ethics and law: Implications of Genome based Medicine

Instructor Dr. J.N.G.M. van Dartel and Mr. dr. R.E. van Hellemondt (Medical Ethics and Law

department, LUMC)

Goal Student receive an introduction on the ethical implications of Genome based

Medicine

Working group 10.00 – 12.30

Title Transhumanism and other images of the future.

Instructor Dr. J.N.G.M. van Dartel and Mr. dr. R.E. van Hellemondt (Medical Ethics and Law

department, LUMC)

Goal The student can explain how Genome Based Medicine is related with philosophical

views of humankind and its future. The student can explain what the impact is of

these technological images of medicine on the patient-physician relationship.

Self-study 13.00 – 17.00

Title Genetics and Genomics: Impact on Medicine and Society.

Goal The student can describe the changes in orientation in modern medicine and

critically reflect on the pros and cons of this development. The students have to

write a short paper (350 words) about the pros and the cons regarding the

developments in medicine.

Literature - Norgren A, Responsible Genetics. The Moral Responsibility of Geneticists for the

Consequences of Human Genetics Research, blz 218 – 223.

29

- McKenny GP, The ethics of Regenerative Medicine: Beyond Humanism and

Posthumanism, in: Ip KT, (editor) The Bioethics of Regenerative Medicine, blz.155-

169.

Friday September 19

Patient Demonstration 9.00 – 9.45

Instructor Prof.dr. A. Tibben (Clinical Genetics department, LUMC).

Title Practical and emotional implications of a severe genetic disease

Goal In this patient demonstration the student learns the practical and emotional

implications of being confronted with a severe genetic disease.

Working group 10.00 – 12.30

Title Family Dynamics.

Instructor Prof. dr. A. Tibben (Clinical Genetics department, LUMC), Dr. J.N.G.M. van Dartel

and mr. dr. R.E. van Hellemondt (Medical Ethics department, LUMC)

Goal The student takes part in a role-play game that demonstrates the impact of

Huntington Disease on a family.

Self-study 13.00 – 17.00

Ethics and tasks.

Title Incidental findings.

Goal The student can explain the values and norms concerning incidental findings in

counselling and medical practice and reflects on his own position in this matter, for

instance regarding giving feedback to tested patients and expecting parents.

The students have to answer some questions in order to prepare for working group

‘incidental findings’ on Thursday 25 September.

Literature - Bredenoord AL, Onland Moret NI, Van Delden J, Feedback of individual

genetic results to research patients: in favour of a qualified disclosure policy, in:

Human Mutation 32(2010): 861-867.

- Search for relevant literature in Pudmed

- American Academy of Pediatrics, Committee on Bioethics, Committee on Genetics,

and American College of Medical Genetics and Genomics Social Ethical and Legal

Issues Committee. 2013.

Policy statement: Ethical and policy issues in genetic testing and screening of

children. Pediatrics 131(3): 620–622.

Monday September 22

Practical 9.00 – 10.00

Title DNA isolation


Goal Students will isolate their own DNA from the saliva samples taken previously

Tour 10.00 – 11.00

30

Title LGTC/Sequencing facility tour


Goal Students will visit LGTC/Sequencing facility while their DNA is dissolving

Practical 11.00 – 12.00

Title DNA quantification


Goal Students will quantify their DNA.

Self-study 13.00 – 14.00




Practical 14.00 – 15.00

Title PCR setup for DNA profile & SNV test


Goal Students will set up PCR reactions for the DNA profile & SNV tests.


Lecture 9.00 – 9.45

Title Transcriptomics, proteomics, metabolomics

Instructor Dr. P.A.C. 't Hoen (Human Genetics department, LUMC)

Goal Biomarkers are measurable molecular entities that serve as indicators of normal

biological or pathological processes. New –omics technologies are increasingly used

to identify RNA, protein or metabolite biomarkers in body fluids such serum or urine.

These biomarkers may be used in differential and early diagnosis, and in monitoring

of disease progression or therapeutic response. In this lecture, the technologies for

biomarker identification will be discussed. Moreover, with Duchenne Muscular

Dystrophy as an exemplar disease, it will be shown how molecular biomarkers can

support clinical measures in clinical trials for new drugs.

Lecture 10.00 – 10.45

Title The future hospital, personal monitoring

Instructor Prof. dr. M.H. Breuning (Clinical Genetics department, LUMC)

Goal Personalized medicine is expected to benefit from combining genomic information

with regular monitoring of physiological states by multiple high-throughput methods.

An integrative personal omics profile (iPOP), an analysis that combines genomic,

transcriptomic, proteomic, metabolomic, and autoantibody profiles from a single

individual can be used to interpret healthy and diseased states by connecting

genomic information with additional dynamic omics activity. It is expected that this

form of monitoring will revolutionize health care in the near future.

Contact 11.00 – 11.45

31

Title My genome sequence

Instructor Dr. M. Kriek (Clinical Genetics department, LUMC)

Goal Q & A session on genome sequence topic

Preparation (paper placed on Blackboard)

Practical 13.00 – 16.00

Title DNA profile & SNV test


Goal Students will analyze PCR products for the DNA profile & SNV tests. The DNA profile

will be analysed using the Qiaxcel system; the SNV test using High Resolution Melting

Curve Analysis.


Assessment 13.30 – 17.00

Title Oral presentations of students

Instructors Prof. dr. P. de Knijff (FLDO, Human Genetics department, LUMC), Dr. H. Sminia

(Human Genetics department, LUMC)

Goal Each student will give an oral presentation on Knowledge from genome that has

been prepared in weeks 3 & 4.


Lectures 9.00 – 12.15

Title Ethics and Law: Incidental findings

Instructor Dr. M. Kriek (department of Clinical Genetics, LUMC), mr. dr. R.E. van Hellemondt

and Dr. J.N.G.M. van Dartel (Medical Ethics department, LUMC)

Goal Students receive an introduction on ethical and legal aspects of incidental findings

identified by whole exome and whole genome sequencing.

Students receive information on how to handle incidental findings in a diagnostic -

and in a scientific setting

Practical 13.00 – 17.00

Title Ethics and Law: The future of neonatal screening

Instructor Dr. M. Kriek (Clinical Genetics department, LUMC), mr. dr. R.E. van Hellemondt

and dr. J.N.G.M. van Dartel (Medical Ethics and Law department, LUMC)

Goal The students will be invited to discuss some ethical and legal issues of neonatal

screening. The students will summarise the outcome of the discussion in a short

report. In this report, the students will describe both the pros and the cons of

extending neonatal screening by including untreatable (non-actionable disorders)

diseases . Finally they will ‘advice the health council” about the future of neonatal

screening.

Friday September 26

32

Lectures 9.00 – 16.00 with a break (1 hour)

Title Ethics and law: Commercial screening

Instructor Dr. M. Kriek (Clinical Genetics department, LUMC), mr. dr. R.E. van Hellemondt en

Dr. J.N.G.M. van Dartel (Medical Ethics and Law department, LUMC)

Goal Student receive an introduction on ethical and legal aspects of genetic screening,

population surveys and direct-to-consumer testing.

Students will learn to write a reader’s letter on an actual screening issue.

Contact 16.00 – 17.00

Title Evaluation with students

Instructors Dr. J.N.G.M. van Dartel (Medical Ethics department, LUMC), Dr. M. Kriek (Clinical

Genetics department, LUMC)

Goal Evaluation of ethics and legal tasks.

33

Theme3:Gene(s)&environment


coordinators: Prof.dr. ir. J.A.P. Willems van Dijk (HG) and Dr. P.A.C. 't Hoen (HG)

Other teachers involved: Prof.dr. C.J. van Asperen (CG), Prof.dr. R. Fodde (Erasmus MC), Dr. V.J.A.

van Harmelen (HG), Dr. K.M. Hettne (HG), Prof.dr J.J. van Hilten (Neuro),

Prof.dr. A.M.J.M. van den Maagdenberg (HG), Dr. E.C. Robanus Maandag

(HG), Dr. M. Kriek (CG), Prof.dr. H. Pijl (Endo), Dr. M. Roos (HG), Prof. dr.

P. Slagboom (Epi), Dr. G.M. Terwindt (Neuro), Dr. E.A. Tolner (HG), Dr.

M.P.G. Vreeswijk (HG), Dr. H. Vrieling (Tox), Dr. B. de Vries (HG)

Complex diseases, such as type 2 diabetes, migraine and Parkinson’s disease, are also called

polygenic diseases since they are usually not caused by mutations in a single gene but a result of a

set of genetic predispositions and their interplay with environmental factors. This poses significant

challenges that will be addressed in weeks 5 & 6.

We will discuss strategies how to identify genetic contributors to disease. Since any of the individual

factors usually contributes only a small risk, epidemiological studies in large populations are

required. Disease risk is modified by genetic and environmental factors such as microbiota and more

classical risk factors such as obesity, hypertension and smoking. As in complex diseases, the different

contributors to disease seldom act independently but usually form pathways or networks, much of

the focus of week 5 will be devoted on how to identify and study disease-specific pathways, including

approaches to visualize these pathways. Reliable biomarkers, for example proteins that can be

measured in the serum or plasma, can aid physicians in diagnosing their patients. Biomarkers can

also be instrumental to predict disease progression and response to therapy. In the biomarker show

case, the student will take up one the role of one of the important stakeholders, the doctor, the

patient, the researcher, the start-up company founder, or a member of registration board at the

qualification agency.

Based on genetic and molecular information, cellular and animal models can be designed to study

the pathophysiology of complex diseases and strategies to do this type of research will be discussed.

Also the impact of genetic understanding of complex diseases on the clinical counselling and clinical

care will a main focus. This will be illustrated based on four different complex diseases, metabolic

syndrome, migraine, breast and colon cancer. Much attention will be paid to both the clinical and

molecular aspects of these diseases and their prospects for personalized medicine.

Learning objectives and competences:

The student

• Can explain the main principles and pitfalls of genome-wide association studies

• Can use genetic risk prediction in the context of complex disease

• Is able to describe how environmental factors contribute to complex disease

• Is able to perform pathway analyses based on genetic findings

• Can play the role of different stakeholders in bringing biomarker assays to the market

• Can translate genetic knowledge to meaning full cellular and animal disease models

• Can use genetic knowledge of gene-function in cellular assays for breast cancer


- Lectures on complex genetics and genome wide associations, i.e. migraine, breast cancer.

- Discussion on 23&me profile - what can we derive from a risk profile for complex diseases –

Alzheimer as example.

34

- Lectures and working groups on the role of genes and environment in disease, i.e. cardio

vascular disease, migraine, metabolic syndrome, colon cancer.

- The design of a questionaire on familial risk assessment.

- A ‘role play’ to learn the points of view of different parties involved in the discovery and

qualification of biomarkers for polygenic diseases.

- Working groups on pathway analysis and functional studies for assigning functions to genetic

variants in complex disease.

Contact hours (27 hours over 10 days): e.g. designing a questionnaire, patient demonstrations

Interaction hours (15 hours over 10 days): e.g. risk profiling, panel discussion, workgroup

Self-study hours (10 hours): e.g. risk prediction assignment, preparation for migraine lecture,

Evaluation:

-risk prediction assignment (group feedback; ‘responsie college’)

-Gene to Disease test: variant annotation [INDIVIDUAL OFFICIAL EVALUATION]

- Anamnesis test [INDIVIDUAL OFFICIAL EVALUATION]

-Role play in biomarker show case assignment (group feedback)

-Migraine workgroup (group feedback)

-Design questionnaire for familial risk assessment (group feedback)


Chapters 8-10, 11, 12, 15, 20, 21, 23 Emery’s Elements of Medical Genetics, by P. Turnpenny, S. Ellard

35




9.00-10.00 Introduction: genetics of complex disease (family risk) Lecture Prof. K. Willems van Dijk

10.15-11.00 GWAS studies (principles plus platforms (array and NGS) explained) Lecture Dr. P-B. 't Hoen

13.00-14.00 Introduction Parkinson Lecture Dr. H. Marinus

14.00-16.00 23&me profile - what can we derive from a risk profile for complex diseases - Parkinson Practical Dr. P-B. 't Hoen


9.00-10.00 Introduction gene - environment interactions (microbiotica) Lecture Prof. K. Willems van Dijk

10.15-11.15 Risk prediction: Cardiovascular disease Lecture Dr. M. Beekman

13.00-16.00 Self study - reading of review + answering questions Self study Prof. K. Willems van Dijk

16.00-17.00 Reflection on selfstudy Contact Prof. K. Willems van Dijk

Wednesday October 1

9.00-10.00 Introduction pathway / network analysis Lecture Dr. K. Hettne

10.15-11.15 GWAS and pathway analysis - migraine as example Lecture Dr. B. de Vries

13.00-15.30 Pathway visualization / network analysis Practical Drs. M. Roos & K. Hettne

15.30-16.30 Gene to disease task + anamnesis Assessment Dr. P-B. 't Hoen and Dr. M. Kriek

Thursday October 2

9.00 -10.00 Introduction show cases: discovery and qualification of biomarkers for polygenic diseases Lecture Dr. P-B. 't Hoen

10.00-15.00 Self study / preparation Role play Dr. P-B. 't Hoen

15.00-17.00 Presentations by groups: assessment of arguments by the group and by the instructors Contact Dr. P-B. 't Hoen

Friday October 3 “Leidens ontzet” no course today


Week 6 Monday October 6

9.00-10.00 Genetic Susceptibility to Breast Cancer Lecture Dr. M. Vreeswijk

10.15-11.15 Breast cancer in the family: clinical genetic aspects Lecture Prof. C. van Asperen

11.15- 12.15 Testing genetic variants of unknown significance in functional cellular assays Lecture Dr. H. Vrieling

13.00-16.00 DNA sequence analysis in breast cancer families; how to determine clinical significance Practical Dr. H. Vrieling and Dr. M. Vreeswijk

Tuesday October 7

9.00-10.00 Clinical introduction metabolic syndrome Lecture Prof. H. Pijl

10.15-11.15 Inflammation in Metabolic Syndrome Lecture Dr. V. van Harmelen

13.00-16.00 Self study: papers migraine Self study Prof. A. van den Maagdenberg

17.00 Deadline questions for lecture on the following day Self study Prof. A. van den Maagdenberg

Wednesday October 8

9.00-10.00 Clinical introduction migraine Lecture Dr. G.Terwindt

10.15-11.15 Functional studies in mouse models Lecture Prof. A. van den Maagdenberg

13.00-17.00 Working group migraine functional & genetics Working group Drs. E. Tolner / B. de Vries

Thursday October 9

9.00 -10.00 Mouse models for colon cancer Lecture Prof. dr. R. Fodde

10.15-11.15 Microbiome as an environmental risk modifier of colon cancer Lecture Dr. E. Robanus-Maandag

13.00-16.00 Self study

16.00-17.00 Discussion of review by students Working group Dr. E. Robanus-Maandag

Friday October 10

9.00 -10.00 Introduction show case: unravelling the heriditary components of complex disorders Lecture Prof. C. van Asperen

10.15 -17.00 Show case: Design a questionaire on familial risk assessment Working group Prof. C. van Asperen

36

Monday September 29

Lecture 9.00 – 10.00

Title Introduction: genetics of complex disease (family risk)

Instructor Prof.dr. K. Willems van Dijk

Goal Both type 2 diabetes and cardiovascular disease are highly heritable as evidenced by

the dramatically increased risk for subjects with young affected relatives in the first

degree. A small proportion of this family risk is explained by monogenic inheritance.

However, the inheritance pattern of the risk in the majority of families is not

monogenic but complex. In this lecture, examples of genetic complex disease and

their interaction with environmental factors will be discussed.

Lecture 10.15 – 11.00

Title GWAS studies (principles plus platforms (array and NGS) explained)

Instructor Dr. P.A.C. 't Hoen

Goal Genome-wide association studies (GWAS) are powerful methods to identify genes

that explain the heritability of complex diseases. The identified genes frequently

provided new insights in the aetiology of the disease. In this lecture the principles of

GWAS, the molecular technology and the analysis methods will be explained. The

novel biological insights in diabetes, obtained through GWAS, will be discussed.

Lecture 13.00 – 14.00

Title Introduction Parkinson

Instructor Prof.dr. J. J. van Hilten

Goal Parkinson is a disease where GWAS has provided important insights in the molecular

pathways involved in the disease. The different clinical manifestations, genetic basis

and molecular pathways involved will be discussed. An overview of the clinical

research on Parkinson’s performed at LUMC will be given.

Practical 14.00 – 16.00

Title 23andMe profile - what can we derive from a risk profile for complex diseases -

Parkinson


Goal 23andMe provides a molecular genetic tests to regular consumers without

intervention of a clinician. The report provided to the customer contains a risk

prediction for the development of complex diseases like Parkinson. Here we learn

how these risk scores are calculated, how they should be interpreted, and what the

potential impact of these tests on customers and their treating clinicians could be.


Lecture 9.00 – 10.00

Title Introduction gene - environment interactions (microbiota)

Instructor Prof.dr. K. Willems van Dijk

Goal The microbiome, encoded by all microorganisms in and on our body, has also been

termed our second genome. For example, there are 10 times more bacteria in our

gut than we have cells. These bacteria are not just bystanders, but function in the

37

harvest of energy from our food and play a role in the development and

maintenance of the immune system. Gut microbiota have been associated with

metabolic and immune disorders and could function as targets for intervention. In

this lecture, recent insight into the role of gut microbiota in metabolic and

cardiovascular disease will be discussed.

Lecture 10.15 – 11.15

Title Risk prediction: Cardiovascular disease

Instructor Prof.dr. P. Slagboom (Dept. of Molecular Epidemiology)

Goal This lecture will explain the principles behind the calculations used in risk

predictions. More and more, the genetic make-up of an individual is used to

calculate disease risk. As an example, the burden test is used to combine the relative

risks from individual genetic loci into an aggregate genetic risk score. This, and the

relative merits and complementarity of classical (such as body mass index), genetic

and metabolic risk scores will be discussed in the context of the mortality from

cardiovascular disease.

Selfstudy 13.00 – 16.00

Title Reading review and answering questions

Literature Sommer F & Bäckhed F. The gut microbiota--masters of host development and

physiology. Nat Rev Microbiol. 2013;11(4):227-38

Contact 16.00 – 17.00

Title Reflection on selfstudy

Instructor Prof.dr. K. Willems van Dijk (Dept. Human Genetics)

Goal Discussion of selfstudy Sommer F & Bäckhed F paper.

Wednesday October 1

Lecture 9.00 – 10.00

Title Introduction pathway / network analysis

Instructor Dr. K. Hettne (Dept. Human Genetics)

Goal The interplay between an array of molecular factors lies at the basis of complex

diseases. Previously, genes were studied mostly in their isolation. More recently,

pathway and molecular network analysis methods have been developed that study

the concerted action of sets of genes, proteins and metabolites. This has two

important advantages: joint analyses are more powerful and joint analyses make

results better interpretable. An overview of molecular pathway and network-based

approaches to reveal the genetic basis of complex diseases will be given.

Lecture 10.15 – 11.15

Title GWAS and pathway analysis - migraine as example

Instructor Dr. B. de Vries (Dept. Human Genetics)

38

Goal Overview of the use of GWAS to identify migraine genes. The lecture will highlight

which genes have been identified in which patient groups and how knowledge on

mechanisms involved in the pathophysiology of migraine is achieved.

Practical 13.00 – 15.30

Title Pathway visualization / network analysis

Instructors Dr. M. Roos and Dr. K. Hettne (Dept. Human Genetics)

Goal In this computer practical the student will get to know bioinformatics tools that help

to visualize molecular pathways and networks underlying complex diseases.

Projection of results from large molecular datasets onto these pathways or networks

will facilitate the interpretation of these datasets and help to identify critical proteins

in these pathways and potential druggable targets.


Title Gene to disease task + anamnesis

Instructors Dr. P.A.C. 't Hoen and Dr. M. Kriek

Goals In the gene to disease task, the student will receive a set of genetic variants and

evaluate their potential involvement in disease.

Preparation The student should review which characteristics discriminate genetic variants with

functional impact (such as their involvement in monogenic or complex disease) from

‘neutral’ genetic variation.

Thursday October 2

Lecture 9.00 – 10.00

Title Introduction show cases: discovery and qualification of biomarkers for polygenic

diseases


Goals Biomarkers are molecular characteristics that can be used to determine disease

susceptibility, disease progression or response to therapy. Determination of

biomarker levels may help to individualize clinical care. An introduction on molecular

biomarkers will be given, followed by the introduction of the case study. The case

study will reflect the optimization of strategies for biomarker discovery and the route

towards authorization of biomarkers in clinical practice.

Role play 10.00 – 15.00

Title Self-study / preparation

Goal Students will be divided in groups with different roles: researcher, doctor, business

developer, patient, qualification agency (FDA / EMA). From these different

perspectives, the students will research the potential and added value of a given

biomarker for the current clinical practice and prepare a presentation for the whole

group where they argue for or against its introduction in clinical practice.

39

Contact 15.00 – 17.00

Title Presentations by groups: assessment of arguments by the group and by the

instructors

Instructors Dr. P.A.C. ’t Hoen & Prof. dr. K. Willems van Dijk

Goal Students will present what they have prepared for the assessment.

Friday October 3

“Leidens ontzet” so no course today

Monday October 6

Lecture 9.00 – 10.00

Title Genetic Susceptibility to Breast Cancer

Instructor Dr. M. Vreeswijk

Goal Since the discovery of BRCA1 and BRCA2 the search for additional breast cancer

susceptibility genes is ongoing. Depending on the associated breast cancer risk,

different methodologies are used for the identification of these genes. The function

of the genes will be discussed as well as the opportunities for personalized

healthcare.

Lecture 10.15 – 11.15

Title Breast cancer in the family: clinical genetic aspects

Instructor Prof.dr. C. van Asperen

Goal Overview of hereditary aspects of breast cancer: which genes are involved and how

is this knowledge applied into clinical practice (genetic counselling, screening high

risk groups, preventive surgery)

Lecture 11.15 – 12.15

Title Testing genetic variants of unknown significance in functional cellular assays

Instructor Dr. H. Vrieling

Goal High-throughput sequence analysis in patients with hereditary forms of cancer is

yielding a rapidly increasing number of genetic variants in cancer-predisposing genes

for which the clinical significance in terms of cancer risk is unknown. Functional

cellular assays have been developed to determine the impact of these variants on

gene function.

Practical 13.00 – 16.00

Title DNA sequence analysis in breast cancer families; how to determine the clinical

significance

Instructors Dr. M. Vreeswijk and Dr. H. Vrieling

Goal Many DNA alterations are identified during DNA sequencing in breast cancer

families. Students will learn how to use and interpret web-based tools to predict

whether certain DNA variants will affect protein function. Based on pedigree

information they have to decide which additional research should be commenced in

the family and which screening guidelines should be advised.

40

Tuesday October 7

Lecture 9.00 – 10.00

Title Clinical introduction metabolic syndrome

Instructor Prof.dr. H. Pijl

Goal Modern humans are severely mismatched with their nutritional environment, which

has resulted in a worldwide epidemic of obesity. Obesity is the driving force of the

metabolic syndrome, which is characterize by the co-occurrence of several metabolic

and vascular risk factors, associated with an increased risk for type 2 diabetes and

cardiovascular disease. In this lecture, the obesity epidemic will be discussed by

considering nutrition in the context of human evolution.

Lecture 10.15 – 11.15

Title Inflammation in Metabolic Syndrome

Instructor Dr. V. van Harmelen

Goal Obesity is closely associated with insulin resistance, type-2 diabetes (T2DM),

dyslipidemia, hypertension and cardiovascular disease. Expanding white adipose

tissue plays an important role in the patho-physiology of obesity associated disorders

as it responds to the energy overload with stress signals which in turn can elicit local

immune responses and inflammation. In my lecture I will describe the underlying

mechanisms for inflammation in white adipose tissue.

Selfstudy 13.00 – 15.00

Title Reading papers migraine & preparing questions for the lecture of Prof Dr. A.M.J.M.

van den Maagdenberg on Wednesday October 8

Goal After detailed reading each student prepares at least one relevant question that will

be addressed in the lecture of Prof Dr. A.M.J.M. van den Maagdenberg on

Wednesday October 8

Preparation De Vries B et al. “Molecular genetics of migraine” Hum Genet 2009;126:115-32.

van den Maagdenberg AM et al. “Migraine: gene mutations and functional

consequences” Curr Opin Neurol. 2007; 20(3):299-305.

Selfstudy 15.00 – 16.00

Title Reading papers migraine & preparing questions for Working group migraine

functional and genetics on Wednesday October 8

Goal Students are prepared for the Working group Migraine

Preparation Eising E et al. “Pearls and pitfalls in genetic studies of migraine” Cephalalgia 2013;

33(8):614-25; Charles A. Migraine: a brain state. Curr Opin Neurol. 2013

Jun;26(3):235-9

Contact 17.00

Title Deadline for sending in question lecture () on the following day

Instructor Prof.dr. A.M.J.M. van den Maagdenberg

41

Goal Each student sends at least one relevant question Prof Dr. A.M.J.M. van den

Maagdenberg by email ([email protected])

Wednesday October 8

Lecture 9.00 – 10.00

Title Clinical introduction migraine

Instructor Dr. G. M. Terwindt

Goal Migraine is a chronic, paroxysmal, neurologic disorder, characterized by severe

unilateral pulsating headache. Two types of migraine are distinguished: migraine

with and without aura. In migraine with aura, headache attacks are preceded or

accompanied by visual disturbances. In this lecture we will discuss the classification

and diagnosis of different forms of migraine.

Lecture 10.15 – 11.15

Title Functional studies in mouse models

Instructor Prof.dr. A.M.J.M. van den Maagdenberg

Goal Familial forms of severe migraine have led to the discovery of genes that play a role

in the etiology of a migraine attack. These genes have modified in mouse models and

these models provide novel insight into the underlying triggers for and mechanisms

of migraine. Migraine mouse models and functional studies to gain insight into

migraine will be discussed.

Workgroup 13.00 – 17.00

Title Working group migraine functional and genetics

Instructors Dr. E.A. Tolner and Dr. B. de Vries

Goals After a 15 min introduction about the working groups (13:00 – 13:15), the students

will be split into 2 groups of max 8 students. One working group will cover the

genetics of migraine and the other working group the functional mechanisms

involved in migraine, after 1,5 hour the students will switch groups.

The genetic working group will cover the identification of genetic factors for common

migraine. Genome-wide association studies (GWAS) are a typical approach to

identify these factors and have been very successful for migraine. An example for

migraine without aura (MO) will be discussed, and students will learn about the

clinical and methodological challenges involved in these studies (e.g. the difference

between clinic-based and population-based diagnoses) and the relevance of the

GWAS results for migraine patients.

The functional working group will cover underlying mechanisms of migraine, with

focus on changes in neuronal excitability and migraine susceptibility caused by

human pathogenic mutations. Migraine-relevant readouts will be discussed that

including the phenomenon of cortical spreading depression (CSD), the

neurobiological mechanism underlying the migraine aura. Students will learn to

recognize the effect of altered neuronal excitability, gender and a common migraine

trigger stress on the migraine-relevant readout CSD.

Preparation See self-study instructions for Tuesday October 7 2014

42

Thursday October 9

Lecture 9.00 – 10.00

Title Mouse models for colon cancer

Instructor Prof.dr. R. Fodde

Goal Familial forms of colon cancer have led to the discovery of genes that play a role in

the etiology of colon cancer. These genes have modified in mouse models and these

models provide novel insight into the underlying triggers for and mechanisms of

colon cancer. Colon cancer mouse models and functional studies to gain insight into

colon cancer will be discussed.

Lecture 10.15 – 11.15

Title Microbiome as an environmental risk modifier of colon cancer

Instructor Dr. E. Robanus Maandag

Goal Intestinal microbes protect against enteropathogens, extract nutrients and energy

from diets, and contribute to normal immune function. Disruptions to the normal

balance between the intestinal microbiota and the host can contribute to

susceptibility for diseases such as obesity, fatty liver disease, type 1 and 2 diabetes

and kidney disease. In this lecture, the role of microbiota in the development of

colon cancer will be discussed.

Selfstudy 13.00 – 16.00

Preparation Sears and Garrett. “Microbes, microbiota, and colon cancer”. Cell host & Microbe

2014; 15:317-328. Walsh et al. “Beneficial modulation of the gut microbiota”. FEBS

Lett. 2014; doi: 10.1016/j.febslet.2014.03.035.

Goal After detailed reading each group of 2 students can explain to the other students the

essentials of any paragraph of both papers.

Workgroup 16.00 – 17.00

Title Discussion of review by students

Instructor Dr. E. Robanus Maandag

Goal Each student knows the recent insights into the contributions of gut microbiota to

colon cancer and into beneficial modulation of these microbiota.

Friday October 10

Lecture 9.00 – 10.00

Title Introduction show case: unravelling the hereditary components of complex disorders

Instructor Prof.dr. C. van Asperen

Goal Pedigrees are a starting point for making a diagnosis hereditary cancer. Cases will be

discussed in order to decide if further investigations will be recommended.

Workgroup 10.15 – 15.00

Title Show case: Design a questionnaire on familial risk assessment

43

Goal Students will form groups and write a short introduction on family risk as

information for patients for different diseases: colon cancer, breast cancer, diabetes,

cardiovascular disease etc. (1 disease per group). In addition the questionnaire is

designed in a patient friendly manner.

Contact 15.00 - 17.00

Title Show case: Design a questionnaire on familial risk assessment

Instructors Prof.dr. C. van Asperen and Prof.dr. K. Willems van Dijk

Goal Students will present the short introduction on family risk as information for patients

and the questionnaires.

44

Theme4:

Personalgenomics:pharmacogenomics&genetictherapies


coordinators: Prof.dr. H.J. Guchelaar (CP) and Dr. A.M. Aartsma-Rus (HG)

Other teachers involved: Dr. P. Bank (CP), Prof.dr. M.H. Breuning (CG), Prof.dr. A.J. Gelderblom

(CO), Dr. P.C. Giordano (CG), Dr. C.L. Harteveld (CG), Dr. J. den Hartigh

(CP), Dr. K. Janssen (CG), Prof.dr. J.-L. Kerkhof (EUR), Dr. M. Lolkema (CO,

UMCU), Dr. M. Phylipsen (CG), Dr. J. Rens (Prosensa Therap.), Dr. J.J.

Swen (CP), E. Vroom (DMD Patient Association)

In this part of the course the topics of pharmacogenomics (week 7), health prevention screening

(week 7 & 8) and genetic therapies (week 8), which together form the core of Personalized medicine,

are covered.

Individual genetic variation and mutations cause genetic diseases and increase the risk for

developing complex diseases. Pharmacogenomics studies how genetic variation may also result in an

altered individual drug response, which can have serious implications for treating patients. The

potential problem is serious as genetic variation accounts for no less than 20-95% of the variability in

drug response. Drug response is complex with significant inter-patient variability with poor drug

efficacy as a main outcome. Even more dramatic, if pharmacogenomics is not taken into account,

patients may suffer from serious adverse events of using drugs that can directly affect the health of

patients, but could have been prevented. Needless to say that treating physicians should be made

well aware of the principles of pharmacogenomics and how genetic variation can affect treating their

patients. Fortunately, pharmacogenomic information is accumulating rapidly for an increasing

number of drugs and this will certainly impact clinical care more and more over the next few years.

Several consortia have published guidelines to aid physicians and pharmacists with the interpretation

of pharmacogenetic test results and multiple medical centers have initiated prospective genotyping

programs for “pharmaco-genes”.

DNA technology also has an impact on health prevention, for instance by neonatal screening of

newborns for a number of serious congenital diseases and/or diseases that can be treated if the

physician and parents are aware of the disease risk in the child. Hemoglobinopathies are good

examples of related monogenic diseases in blood for which health prevention screening is being

applied. Not unimportant, current therapeutic options for hemoglobinopathies have shortcomings

that are addressed in the course. Disease burden in patients and their families as well as the

economic burden due to expensive treatment has led to the implementation of prevention programs

in many countries where hemoglobinopathies are endemic. Also in The Netherlands

hemoglobinopathies is an increasing health problem. In our multi-ethnic population counselling and

primary prevention is an important strategy to tackle this problem. From 2007, Sickle Cell Disease

has been added to the list of diseases checked for in the heel-prick screening. It is one of the few

genetic diseases that can easily be screened by relatively simple and cheap biochemical methods

instead of the more expensive DNA screening. Benefits and pitfalls of offering screening for a genetic

disease, such as hemoglobinopathies, to the public will be discussed.

Molecular knowledge has the potential to lead to targeted therapies to treat disease, so-called

genetic therapies. Different personalized medicine approaches are in development, including gene

therapy, cell therapy, exon skipping, stop codon read-through and up-regulation of homologous

genes. Notably, the exon skipping approach can be exploited in different ways for different genetic

conditions, including Duchenne muscular dystrophy. Performing clinical trials for personalized

45

medicine approaches is challenging, especially when trials are performed in children. The main

technologies of genetic therapies, the perspectives of the researcher, the patient, and industry are

discussed in this part of the course, as well as the ethical considerations that link to dealing with sick

patients in drug testing.


The student

• Can identify the opportunities and challenges of different gene therapy approaches.

• Is able to critically review different gene therapy approaches.

• Can reproduce how exon skipping can be exploited for different diseases.

• Is able to discuss the key aspects of clinical trials from various stakeholder perspectives.

• Can give an example of how screening for a common monogenic disease can be offered

to the public.

• Can discuss various therapies and their limitations to prevent hemoglobinopathies.

• Is able to define the reasons and benefits for genetic population screening.

This part of the course will include various specific topics:

- Various introductory lectures on, a) pharmacogenomics and pharmacogenetics that are

important to understand how genetic variation can alter drug response (i.e. drug efficacy and

adverse events), b) health prevention screening (taking hemoglobinopathies as the example),

and c) genetic therapies (e.g. exon skipping as a promising molecular approach to design

therapy).

- Specific disease-targeted lectures and practical lectures that discuss how therapeutic drug

monitoring and drug intervention is performed in clinical practice

- Several hands-on topics, including preparing CYP2D6 student-specific drug passports, generating

a Wikipedia page, and a exon skip[ping workshop.

- A student debate on ethical aspects of therapy development.

Contact hours (8 hours), divided over 8 days: e.g. feedback on Wikipedia page, student debate

Interaction hours (28 hours), divided over 8 days: e,g. practicals, exon skipping workshop

Self-study hours (17 hours): e.g. preparing Wikipedia page, preparing for student debate

Evaluation:

- Wikipedia page assignment (feedback per student group). Pass/ no-pass

- CYP2D6 drug passport assignment (feedback per student group). Pass/ no-pass

- Student debate on ethical aspects of therapy development (group feedback)


Chapters 8, 10, 12, 20, 23 Emery’s Elements of Medical Genetics, by P. Turnpenny, S. Ellard

46




9.00-10.00 Introduction - Individualized Medicine "One size fits all" Lecture Prof. H.-J. Guchelaar

10.15-11.00 Basic pharmacokinetics and dynamics - a refresher Lecture Dr. J. Swen

11.15-12.00 Therapeutic drug monitoring in clinical practice Lecture Dr. J. den Hartig

12.00-13.00 Pharmacogenetics - Examples from clinical practice Lecture Prof. H.-J. Guchelaar

13.00-16.00 Planning: generating a Wikipedia page - hand out assignments Self study Dr. J. Swen

Tuesday October 14

10.15-11.15 Clinical application of pharmacogenetics Lecture Dr. J. Swen

11.30-12.30 Oncology pharmacogenetics in the LUMC Lecture/Patient contact Prof. H. Gelderblom

13.30 -14.30 CPCT - Center for Personilized Cancer Treatment Lecture Dr. M. Lolkema, UMCU

14.30-15.30 Self study: Wikipedia page Self study -

Wednesday October 15

9.00-12.00 Practical CYP2D6 genotyping Practical Dr. P. Bank

13.00-16.00 Self study: Wikipedia page Self study -

16.00 Self study: handing in draft version of Wikipedia page Contact Dr. J. Swen

Thursday October 16

9.00-12.00 Results from own genome test on CYP2D6 & preparation CYP2D6 drug passport Practical Dr. J. Swen

15.00-17.00 Discussion on personalized CYP2D6 drug passports Lecture/Patient contact Prof. H.-J .Guchelaar/Dr. J. Swen

Friday October 17

9.00-10.00 Population genetics screening-health prevention Lecture Prof. M. Breuning

10.15-11.15 The clinical example: hemoglobinopathies Lecture Dr. K. Harteveld

13.00-14.00 Clinical & health problem of hemoglobinopathies Lecture Prof. J.L. Kerkhoff, EUR

14.00-17.00 Practical: Hemoglobinopathy diagnostics & counseling Practical Dr. M. Phylipsen



9.00-10.00 Sickle cell disease: a growing problem in The Netherlands Lecture Dr. K. Harteveld

10.15-11.15 Prevention strategies of hemoglobinopathies Lecture Dr. P. Giordano

13.00-16.00 Feedback to students on draft Wikipedia page + continuing optimisation Contact/Self study Dr. J. Swen

TuesdayOctober 21

9.00-10.00 Introduction on genetic therapies Lecture Dr. A. Aartsma-Rus

10.15-11.15 Assignment on genetic therapies Workgroup Dr. A. Aartsma-Rus

13.00-16.00 Literature assignment therapies Self study -

16.00-17.00 Discussion on genetic therapies for Duchenne muscular dystrophy Contact Dr. A. Aartsma-Rus


9.00-9.30 Introduction on exon skipping Lecture Dr. A. Aartsma-Rus

9.45-12.00 Workshop exon skipping Workshop Dr. A. Aartsma-Rus

13.00-16.00 Ethical aspects of therapy development (based on Youtube movies) Self study -

Thursday October 23

9.30 -16.45 Attend the European Society of Gene and Cell Therapy Conference Conference

Friday October 24

9.00 -10.00 Launching student Wikepedia pages Lecture Dr. J. Swen

10.00 -12.00 Write short report on European Society of Gene and Cell Therapy Conference Workgroup Dr. A. Aartsma-Rus

14.00-15.00 Panel discussion on gene therapy Panel discussion Drs. A. Aartsma-Rus/Harteveld

47

Monday October 13

Lecture 9.00 – 10.00

Title Introduction - Individualized Medicine "One size fits one"

Instructor Prof.dr. H.-J. Guchelaar (Dept. of Clinical Pharmacy and Toxicology)

Goal Introduce the concept of pharmacogenetics and how this may affect

pharmacotherapy.

Lecture 10.15 – 11.00

Title Basic pharmacokinetics and dynamics - a refresher

Instructor Dr. J.J. Swen (Dept. of Clinical Pharmacy and Toxicology)

Goal To update basic knowledge on drug pharmacokinetics and dynamics.

Lecture 11.15 – 12.00

Title Therapeutic drug monitoring in clinical practice

Instructor Dr. J. den Hartigh (Dept. of Clinical Pharmacy and Toxicology)

Goal To explain how currently individualized drug dosing is achieved by therapeutic drug

dosing for several drug classes i.e. antibiotics, anticonvulsive and

immunosuppressive drugs.

Lecture 12.00 – 13.00

Title Principles of Pharmacogenetics

Instructor Prof.dr. H.-J. Guchelaar (Dept. of Clinical Pharmacy and Toxicology)

Goal To explain the background and principles of pharmacogenomics. How can genetic

variation influence drug response?

Contact 13.00 – 16.00

Title Planning: generating a Wikipedia page - hand out assignments


Goal Students will be asked to prepare a Wikipedia page on a pharmacogenomics topic.

To this end they will perform a literature search, analyse and interpret collected

information and explain the pharmacogenomics topic in text that is understandable

to the interested lay public

Tuesday October 14

Lecture 10.15 – 11.15

Title Clinical application of pharmacogenetics


Goal The student will gain insight in the current implementation of pharmacogenetics in

the LUMC. Available guidelines and online resources for pharmacogenomic

information will be discussed.

Lecture 11.30 – 12.30

Title Oncology pharmacogenetics in the LUMC

Instructor Prof.dr. H.J. Gelderblom (Dept. of Clinical Oncology)

Goal The application pharmacogenomics will be discussed from an oncology point of view.

How may germline and somatic variations in DNA be combined to optimize

treatment?

48

Lecture 13.30 – 14.30

Title CPCT - Center for Personilized Cancer Treatment

Instructor Dr. M. Lolkema (Dept. of Clinical Oncology, UMCU)

Goal The mission and work of the Center for Personalized Cancer Treatment to

individualize cancer treatment will be presented.

Selfstudy 14.30 – 15.30

Title Wikipedia page

Goal To work on the Wikipedia assignment.


Contact 9.00 – 12.00

Title Practical CYP2D6 genotyping

Instructor Drs. P. Bank (Dept. of Clinical Pharmacy and Toxicology)

Goal The student will determine his own CYP2D6 genotype.

Selfstudy 13.00 – 16.00

Title Wikipedia page

Goal To work on the Wikipedia assignment.

Contact 16.00

Title Handing in draft version of Wikipedia page


Goal Handing in draft version of the Wikipedia page.

Thursday October 16

Contact 9.00 – 12.00

Title Results from own genome test on CYP2D6 & preparation CYP2D6 drug passport


Goal Based on the available guidelines and his own CYP2D6 genotype the student will

prepare a written report, referred to as CYP2D6 passport.

Contact 15.00 – 17.00

Title Discussion on personalized CYP2D6 drug passports

Instructors Prof.dr. H.-J. Guchelaar & Dr. J.J. Swen (Dept. of Clinical Pharmacy and Toxicology)

Goal Plenary discussion of the CYP2D6 drug passport.

Friday October 17

Lecture 9.00 – 10.00

Title Population genetics screening-health prevention

Instructor Prof.dr. M. Breuning (Dept. of Clinical Genetics)

Goal The presenter will provide the students with the perspective of health prevention

through screening the population for genetic diseases.

Lecture 10.15 – 11.15

Title The clinical example: hemoglobinopathies

Instructor Dr. C.L. Harteveld (Dept. of Clinical Genetics)

49

Goal Providing the students with the necessary background of hemoglobinopathies as an

example of a complex monogenic trait in which prevention benefits from carrier

diagnostics.

Lecture 13.00 – 14.00

Title Clinical/health problem of hemoglobinopathies

Instructor Dr. J.-L. Kerkhoff (Hematologist, HAGA hospital, The Hague)

Goal The presenter will provide the students with background of pathology and current

treatment and curative options for Sickle Cell Disease and beta-thalassemia major.

Contact 14.00-17.00

Title Practical: Hemoglobinopathy diagnostics and counseling

Coordinator Dr. M.Phylipsen (Dept of Clinical Genetics)

Goal The student will learn to interpret lab results and act as a counsellor in performing

risk assessment for HbP-carriers in presumed couples at risk.

Monday October 20 Lecture 9.00 – 10.00

Title Sickle cell disease: a growing problem in The Netherlands

Instructor Dr. C.L. Harteveld (Dept. of Clinical Genetics)

Goal The presenter will explain how immigration can introduce a previously rare genetic

disease into a non-endemic country and change health policies.

Lecture 10.15 – 11.15

Title Prevention strategies of hemoglobinopathies

Instructor Dr. P.C. Giordano (Dept. of Clinical Genetics)

Goal The presenter will introduce the concept of prevention strategies to offer prevention

for severe genetic diseases to society using hemoglobinopathies as an example.

Contact 13.00 – 16.00

Title Feedback to students on draft Wikipedia page + continuing optimisation


Goal Groups of students will receive feedback on the draft Wikipedia page.

Tuesday October 21

Lecture 9.00 – 10.00

Title Introduction on genetic therapies

Instructor Dr. A. Aartsma-Rus (Dept. of Human Genetics)

Goal Introduce different concepts of personalized medicine through genetic therapies to

the students.

Contact 10.15 – 11.15

Title Assignment on genetic therapies


Goal Introduce Duchenne muscular dystrophy and outline the assignment to the students.

For the assignment, students will form groups of 3-4 and will receive 1-2 papers on

different genetic therapy approaches currently in development for DMD. Based on

the paper and literature research the students will have to outline the rationale of

the approach, the most important challenges and opportunities for each approach

50

and have to list for which other diseases the approach could apply as well in a 5-10

minute presentation. Each presentation is followed by a 5 minute discussion. Each

group will have to assign 1 presenter, 1 chair and 1-2 people asking questions to

other groups.

Selfstudy 13.00-16.00

Title Literature assignment therapies

Goal Students have time to read the provided paper and prepare their presentations

Contact 16.00-17.00

Title Discussion on genetic therapies for Duchenne muscular dystrophy


Goal Each group will present their genetic approach as outlined above (1 presenter). The

previous group chairs the presentation and leads the discussion, the following group

has to ask questions (although everyone may ask questions).


Lecture 9.00 – 9.30

Title Introduction on exon skipping


Goal The exon skipping approach is explained to the students

Workshop 9.45-12.00

Title Exon skipping

Coordinator Dr. A. Aartsma-Rus

Goal The students form groups of ~4 students each and have to discuss their assignment,

which involves specific questions on exon skipping for a specific disease. In the last

hour the questions will be discussed by the entire group.

Selfstudy 13.00-16.00

Title Ethical aspects of therapy development

[De kans bestaat dat de studenten op 23 oktober naar de European Society of Gene and Cell Therapy mogen

alwaar een symposium zal plaatsvinden over ethical issues of trial development for rare diseases/children with

rare diseases. Het is op dit moment nog niet duidelijk of dit doorgang zal vinden. Zo ja, dan komt het

programma voor 23 oktober te vervallen, maar blijft het goed dat de studenten zich voorbereiden met deze

zelfstudie.]

Goal The students will be split in 2 equal groups and will have a debate on ethical issues in

involving children in clinical trials, with a focus on DMD (make sure there is at least

one student speaking Dutch in each group as some information is only available in

Dutch, so one student will need to brief the non-Dutch speakers). During the debate

each group will give an oral introduction (5 minutes) highlighting either arguments

against or in favour of performing trials in children, using what happened for DMD as

a showcase.

Things to consider are:

- Burden of participating in a trial for the child

- Informed consent

- Necessity of involving children in trials

- Trials to test safety vs trials to test efficacy of a drug

- Risk/benefit

- Need for multicenter trials for rare diseases

51

In preparation students can watch youtube movies on the impact of Duchenne

muscular dystrophy on daily living

(https://www.youtube.com/watch?v=BoLYm35FKtQ (in Dutch),

http://www.duchenne.nl/nieuws/in-de-media/date/2012 (in English)) and read the

following papers on ethical issues on performing clinical trials in children

(http://issuu.com/betapublishers/docs/medicines_06_2013/23?e=1264402/5910482

(in Dutch) and (http://nieuwsuur.nl/onderwerp/547650-kinderen-als-medisch-

proefpersoon.html) and

http://www.fda.gov/forconsumers/consumerupdates/ucm048699.htm. and this

newspaper article in Dutch on DMD trials that were not allowed in the Netherlands:

http://www.volkskrant.nl/vk/nl/2686/Binnenland/archief/article/detail/330148/200

9/05/09/Kinderen-van-de-rekening.dhtml

These links are a starting point – there is much more information out there.

Thursday October 23

Conference 9.00 – 16.45

Title Attend Conference on Gene and Cell Therapy in The Hague


Goal Attending the European Society of Gene and Cell Therapy will provide the students

the opportunity to attend and international research conference.

Friday October 24

Contact 9.00 – 10.00

Title Launching student Wikipedia pages

Instructors Dr. J.J. Swen (Dept. of Clinical Pharmacy and Toxicology)

Goal Launch and completion of the Wikipedia assignement.

Selfstudy 10.00 – 12.00

Title Write a short report Conference on the Gene and Cell Therapy Conference in The

Hague

Goal The students will write a short report of two lectures they have attended at the Gene

and Cell Therapy Conference in The Hague. The report for each lecture should not be

more than 200 words.

Contact 14.00 – 15.00


Title Panel discussion on gene therapy

Goal Students discuss with the instructor and with each other the possibilities (with pros

and cons) as well as the ethical implication of gene therapy.

52

Theme5:

Literatureassignment:Writingreport&Mini-symposium


coordinators: Prof.dr. D.J.M. Peters (HG), Prof.dr. A.M.J.M. van den Maagdenberg

(HG), Dr. W.M.C. van Roon-Mom (HG)

Other teachers involved: Prof.dr. T. Hankemeier (UvL/LACDR), Prof.dr. S.M. van der Maarel (HG),

Prof.dr. G.J.B. van Ommen (HG)

In the two final weeks (weeks 9 & 10) of the course students will apply their knowledge from the

previous weeks and will write a scientific paper/research proposal under the expert guidance of a

senior researcher. Three experts in the field of genetics will give a mini-symposium highlighting the

important role genetics will play in the clinic in the near future. Students will give an oral

presentation on their scientific research proposal in the closing student symposium.


The student

• Can communicate the acquired knowledge in a written report (“grant proposal”) and oral

presentation in a concise and structured way.

• Can critically assess the content of oral presentations of other student groups.

• Can critically assess the opportunities and limitations of knowing a patient’s full genome.

• Is able to discuss the broad implications of genetics in the future.

This part of the course will include various specific topics:

- Student take part in student group assignments to write a scientific research proposal. Students

closely interact in small groups with an expert researcher to define a relevant clinical problem

and tackle this with a research proposal that uses knowledge acquired in the course.

- Students prepare a written report and an oral presentation on the research topic.

- Several lectures of experts in the field of genetics will shine light on the future landscape of

genetics and how genetics will further add clinicians in treating patients.

Contact hours (6.5 hours over 10 days): e.g. contact expert research on progress of assignments

Interaction hours (15 hours over 10 days): e.g. lectures on future developments in genetics

Self-study hours (~40 hours over 10 days): preparation of written report and oral presentation

Evaluation:

-Written report

-Oral presentation

53




9.00-10.00 Introduction of Topics and senior scientists Contact Peters/Maagdenb/vRoon-M

10.15-11.15 Contact with senior Contact Diverse experts based on disease topic

11.30-17.00 Selfstudy Selfstudy

Tuesday October 28

9.00-10.00 Contact with expert senior scientist Contact Diverse experts based on disease topic

10.00-17.00 selfstudy Selfstudy



Thursday October 30

9.00-10.30 Knowledge Test Assessment Peters/Maagdenb/vRoon-M


Friday October 31



Week 10 Monday November 3


10.00-17.00 Selfstudy Self study

Tuesday November 4


Wednesday November 5 Mini symposium: Genetics of the future

9.00-10.00 Epigenetics and disease Lecture Prof.Dr. S.M. van der Maarel

10.00-11.00 Systems biology and genetic disease Lecture Prof.Dr. T. Hankemeier

11.00-12.00 The future of Genetics Lecture Prof.Dr. G.J.B. van Ommen


Thursday November 6

9.00 -17.00 Self study Self study

-24.00 Deadline for handing in grant proposal Asessment Expert on disease topic

Friday November 7 Symposium with oral presentations

9,00-9,30 Half minor wrap-it-all-up: what have we learnt? Minor coordinators

9.00 -12.30 Presentations Assessment Diverse experts based on disease topic

12.30 - 13.00 Half minor evaluation with students Minor coordinators

54

Monday October 27

Contact 9.00 – 10.00

Title Introduction of Topics and senior scientists

Instructors Prof.dr. A.M.J.M. van den Maagdenberg, PhD; Prof.dr. D.M. Peters, PhD and Dr. W.

van Roon (half minor coordinators)

Goal Explanation about the student task to write a grant proposal and prepare an oral

presentation for the Student Symposium on November 7. Students will receive a

short introduction on the various disease topics and expert senior scientists.

Students will choose one fellow student for the student task and one of the disease

topic. In weeks 9 & 10 the students will work in pairs on the specific disease topic.

Self-study 10.00 – 17.00

Student pairs will have time to prepare the student task (grant proposal and oral

presentation).

Tuesday October 28

Contact 9.00 – 10.00

Title Contact with expert senior scientist

Instructor Expert on specific disease topic of the student pair

Goal Student pairs will meet with the senior scientist to discuss progress of the student

task (grant proposal and oral presentation)

Self-study 10.00 – 17.00


presentation).


Self-study 9.00 – 15.00


presentation).

Thursday October 30


Title Knowledge test



Goals The students will make a written exam with 20 questions that will test the students’

knowledge on genetic technologies, monogenetic disorders, genetic testing in a

clinical routine, genes and environment, pharmacogenetics, genetic therapies and

ethics. The questions link to learning objectives of the course (i.e. both the general

objectives (Knowledge, academic skills, global health, collaboration) and course-

specific objectives).

Preparation Students have studied the course information that is placed on Blackboard

Contact 10.00 – 11.00





55

Friday October 31

Self-study 9.00 – 15.00


presentation).

Monday November 3

Contact 9.00 – 10.00





Self-study 10.00 – 15.30


presentation).

Self-study 15.30 – 17.00


presentation).

Title Reading review and preparing questions for lecture Wednesday November 5

Prof.dr. S.M. van der Maarel (9.00 – 10.00)

Goal Each student has to prepare a question for the lecture based on the article below

Literature van der Maarel SM. Epigenetic mechanisms in health and disease. Ann Rheum Dis.

2008;67 Suppl 3:97-100. de Greef JC, Frants RR, van der Maarel SM. Epigenetic

mechanisms of facioscapulohumeral muscular dystrophy. Mutat Res. 2008;647(1-

2):94-102.

Tuesday November 4

Self-study 9.00 – 15.00


presentation).

Wednesday November 5

Mini symposium: Genetics of the future

Lecture 9.00 -10.00

Title Epigenetics and disease

Instructor Prof.dr. S.M. van der Maarel (head Human Genetics department, LUMC)

Goal In “Epigenetics” heritable changes in gene activity are studied that are not caused by

changes in the DNA sequence. It can also be used to describe the study of stable,

long-term alterations in the transcriptional potential of a cell that are not necessarily

heritable. It becomes more and more clear that epigenetic changes of DNA can cause

human disease. In this lecture a few key diseases, some of which are highly relevant

to clinical care in the LUMC, will be discussed. The students will learn how epigenetic

changes can modify disease mechanisms and provide possible targets for drug

intervention.

Preparation Epigenetic review paper placed on Blackboard

56

Lecture 10.00 – 11.00

Title Systems Biology and genetic disease

Instructor Prof.dr. T. Hankemeier (director Netherlands Metabolomics Center, Leiden

University)

Goal Most biological systems are very complex and involve many proteins, peptides and

metabolites that are tightly regulated. Systems biology is a biology-based inter-

disciplinary field of study that focuses on complex interactions within biological

systems, using a holistic approach (holism instead of the more traditional

reductionism) to biological and biomedical research. A systems biology approach will

aid to better understand disease pathology and goes beyond the dysfunction of a

single gene product. In this lecture it will be made clear what are the main challenges

to measure molecules of various classes and how to study their interaction in

biological systems. Key examples will be presented that will illustrate the need and

power of systems biology in modern genetic research. The students will learn about

the opportunities of systems biology and how it can be used to understand disease

mechanisms and help identifying possible targets for drug intervention.

Preparation Systems biology review paper placed on Blackboard

Lecture 11.00 – 12.00

Title Future of Genetics

Instructor Prof.dr. GJ van Ommen (director of BBMRI, former head department Human

Genetics LUMC)

Goal There are many technical developments in modern genetic research that will cause a

revolution in how patients will be treated by physicians in a few years from now.

Genetic research itself also is developing rapidly with large consortia in which

researchers work together to advance knowledge on a specific disease. The

development of biobanks with large patient samples collected in an organised

manner has turned out a very productive way to perform such research. Physicians

will notice in their day-to-day practice that these new developments will change the

way they diagnose and perhaps even treat their patients. This lecture will paint the

future landscape of genetic research. The students will learn about new

opportunities from genetic developments for taking care of their patients that most

likely have been implemented when they start treating patients themselves.

Contact 13.30 – 14.30





Tuesday November 6

Self-study 9.00 – 17.00


presentation).

Assessment <24.00

Title Deadline for handing in grant proposal


Goal Each student pair needs to complete their grant proposal and send it by email to the

expert senior scientist that has guided them in weeks 9 & 10.

Preparation Grant proposal text: Report of max. 2500 words and 2 illustrations

57

Friday November 7

Student symposium

Lecture 9.00 – 9.30

Title Half minor wrap-it-all-up: what have we learnt?

Instructor Prof.dr. A.M.J.M. van den Maagdenberg (Dept. Human Genetics & Neurology,

LUMC)

Goal Short overview of the course topics in relation to the learning objectives. The

students will see how the different topics of the half minor are interconnected.


Title Oral presentations of student pairs



Goal Each student pair will give an oral presentation on the specific disease topic that

have studied in weeks 9 & 10.

Contact 13.00 – 13.30

Title Half minor evaluation with students



Goal There will be a discussion between students and half minor coordinators to evaluate

the components of the half minor.

from patient dna to personalized medicine · module coordinators: prof. dr. d.j.m. peters human...

Documents