Next generation genomics: translation into clinically useful applications in health care Prof.dr. Martina Cornel Brussels, 14 Nov 2013, Scientific Support to Public Health

2000: genome sequence published Bill Clinton: We are here to celebrate the completion of the first survey of the entire human genome … With this profound new knowledge, humankind is on the verge of gaining immense, new power to heal. Genome science will have a real impact on all our lives -- and even more, on the lives of our children. It will revolutionize the diagnosis, prevention and treatment of most, if not all, human diseases. Collins FS (Right at photo). Nature 2010 & © AP PHOTO/RON EDMONDS

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Future prevention advice?

Common disorders, common variants? Genomics research Shift in research from rare to common disorders Shift from studies on individuals / families to populations Often looking at SNPs (single nucleotide polymorphisms) in genome wide association studies (GWAS) Many statistically significant associations (OR=1.1, 1.2) Hardly any clinical utility

Finding the missing heritability.. Manolio, Nature 2009

Clinical genetics –Huntington and similar automomal dominant conditions –Monogenic subtypes of common complex disorders Public health –Screening programmes (e.g. newborn screening) Oncology, cardiology, etc –Tumor profiling/ tailoring chemotherapy –Recognizing monogenic conditions as cause of sudden death Multifactorial disorders (genes and environmental factors play a role): not ready for applications in health care Genomics in medicine, 2013:

Cancer in the family, young age, often same type –Diagnosis, prognosis and recurrence risk? Counselee has (hereditary) disorder –Diagnosis, prognosis and recurrence risk? Child does not develop adequately (physical abnormalities/ mental retardation) –Diagnosis, prognosis and recurrence risk? Genetics in medicine - Clinical genetics Nascimento, AJHG 2006; 79; 549–555

One gene increases risk of…. Cancer Diabetes –MODY diabetes Cardiovascular disorders –Familiair hypercholesterolemia –Long QT syndrome –HCM

Guidelines in cardiogenetics

11 Sir Muir Gray (Nat Scr Comm UK) All screening programmes do harm. Some do good as well and, of these, some do more good than harm at reasonable cost.

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13 Neonatal screening (heelprick)

New! Whole genome sequencing Nijmegen: in mental retardation of sofar unknown etiology many new diagnoses Analyse any gene?

Ethical challenges Balance pros and cons (beneficence vs. maleficence) –So far DTC genetic testing should not be encouraged (EASAC/FEAM report 2013) –Interest of child central in extending NBS (Cornel et al. EJHG 2013) Allow healthy citizens/ patients to choose for themselves –ESHG calls for prudent use of WGS-based testing (Van El et al. Science 2013) 15

Summary Some (rare) conditions can be predicted better than a decade ago At affordable price But implementation is still ongoing Knowing these conditions can reduce mortality Common disorders often multifactorial – nothing new…. Ethics: do good, (beneficence) do not harm, (non maleficence) allow choice (autonomy) 16

Acknowledgements European Society of Human Genetics European Commission - Tender NBS Centre for Society and the Life Sciences, Nijmegen Center for Medical Systems Biology, Leiden