Genomics and Population Health 26 th January 2006

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

Sequencing of Human Genome Nature 409, 860 -921 (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. ”

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

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

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

Genetic Basis of SCD • Inherited single gene disorders • Autosomal dominant • Heterogeneous • Known genes account for 70 -80% cases • Opportunity for genetic testing H/DCM MYH 7 MYBPC 3 TNNT 2 LQT KCNQ 1 KCNH 2 KCNE 1 KCNE 2 SCN 5 A

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 - 1000 families, 4 members per family • Service includes testing for 3 genes for HCM/ DCM, 5 genes for LQT

Evaluation of Service Clinical SCD Genetic Test Technical Psychological Sociological Ethical Legal Economic 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 Evaluate Effect of Service Genetic test information useful for patient treatment? Clinical Technical Psychological 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 Sociological Ethical Legal Economic Future potential • Use of family history and genetics for prophylactic treatment of LQT • Extent of cascade screening • Molecular correlations to inform patient stratification

SCD-Clinical HCM Family • 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

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

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

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

Rationale for SCD Genetic Testing i) Clinical - common: unmet need : treatable: e. g. HCM 1 in 500 relevance to coronary artery disease difficult clinical diagnoses little systematic “cascade” screening 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

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

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