Jenny Taylor Oxford Genetics Knowledge Park Wellcome Trust Centre for Human Genetics, Oxford, UK Genomics and Population Health 26 th January 2006

Nature 409, (15 February 2001) | Initial sequencing and analysis of the human genome International Human Genome Sequencing Consortium Abstract “The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.” Sequencing of Human Genome

Single gene disorders Complex diseases NHS Regional Genetics Labs Impact of Human Genome Project

OxfordGKP is one of six Genetics Knowledge Parks across the UK, established in 2002 by the Departments of Health and Trade and Industry, “to put Britain at the leading edge of advances in genetics and so transform treatments and services for the benefit of NHS patients”.

Oxford GKP Programmes Sudden Cardiac Death Coronary Artery Disease Learning Disability Colorectal Cancer Oxford GKP Programmes Single gene disorders Complex diseases Sudden cardiac death Coronary artery disease Cancer Learning disability

Sudden Cardiac Death Syndromes Leading cause of sudden death in young people

Sudden Cardiac Death Syndromes Hypertrophic and dilated cardiomyopathies, long QT Prevalence 1:500 (HCM) – 1:10,000 (LQT) Altered cardiac morphology (H/DCM) Arrhythmia (LQT) Leads to syncope, palpitations, heart failure, sudden death

Clinical/Family History ECG 2-D Echocardiography Tissue doppler/MRI Genetic Testing? SCD Current Diagnosis

Genetic Basis of SCD KCNQ1 KCNH2 KCNE1 KCNE2 SCN5A H/DCM MYH7 MYBPC3 TNNT2 LQT Inherited single gene disorders Autosomal dominant Heterogeneous Known genes account for 70-80% cases Opportunity for genetic testing

Oxford GKP SCD Programme Aims 1. Provide a clinical SCD genetic testing service 2. Evaluate effect of service

Provide Clinical Service Established Oxford Regional NHS Genetics Lab as service provider Translated knowledge from research to NHS setting Funded by Oxford GKP Recruitment through Clinical Geneticists Cascade screening families, 4 members per family Service includes testing for 3 genes for HCM/ DCM, 5 genes for LQT

Clinical Technical Psychological Sociological Ethical Legal Economic SCD Genetic Test Evaluation of Service Improved diagnosis/mgt High throughput technology Psychological well-being of those at risk of and with HCM Motivations, experiences, preferences Sharing information in families, testing children IPR issues Cost effectiveness genetic vs clinical testing

SCD – Translation Genetic test information useful for patient treatment? To date Released non-mutation carriers from follow-up Identify need for follow-up where +ve genetics but no clinical signs Promoted change in Clinical Geneticists practice Future potential Use of family history and genetics for prophylactic treatment of LQT Extent of cascade screening Molecular correlations to inform patient stratification Clinical Technical Psychological Sociological Ethical Legal Economic Evaluate Effect of Service

SCD-Clinical Proband diagnosed with HCM from clinical investigations Parents clinically screened –both hypertension and thickened heart muscle Mother more affected – thought to have underlying HCM On genetic testing, father proved to carry mutation, not mother Father’s siblings now recognised to be at risk HCM Family

“Coroners post mortem….provides opportunity to assess the potential risk to the family” Impact of Cardiac National Service Framework Recommendations “Effective evaluation of relatives, guided by genetic testing, can prevent further deaths in he family”

Transfer to NHS Service UK GTN recommendation for LQT ORHT Business Case Commissioner uptake Integration of clinical specialties

Service Implications Patient GP Cardiologist Cardiac Specialist Clinical investigations Genetic Test Clinical Geneticist Post-mortem sample Coroner Affected family

Rationale for SCD Genetic Testing i) Clinical - common:e.g. HCM 1 in 500 relevance to coronary artery disease unmet need :difficult clinical diagnoses little systematic “cascade” screening treatable:beta-blockers / pacemakers ii) Genetic - as a “test case” of complex monogenic disorders: multiple genes and mutations technically demanding genetic classification of sub-types adolescent / adult onset with incomplete penetrance iii) ELSI - immediate ethical issues

Diagnosis Treatment Technicalities Service delivery ELSI Implications for Population Genetics Pre-symptomatic diagnosis Molecular stratification Fast throughput screening of multiple genes Integration of clinical specialties Patient and public demand

Oxford GKP team Sudden Cardiac Death Hugh Watkins (lead) Ed Blair Anneke Seller Kate Thomson Karen Livesey Cassie Fraser-Jones Christina Honeywell Coronary disease Rory Collins (lead) Robert Clarke Alison Palmer Sarah Parish Cancer and learning disability Ian Tomlinson (lead) William Chambers Asa Hedman Ben Honey Angela Jones Sam Knight Regina Regan Kim Smith ELSI and health economics Mike Parker (lead) Tom Barclay Jane Kaye Amy Silver Andrew Smart Sarah Wordsworth Management Jan Duff Jenny Taylor Andrew Wilkie