Transcript Sequencing of Human Genome

Genomics and Population Health
26th 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
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
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
MYH7
MYBPC3
TNNT2
LQT
KCNQ1
KCNH2
KCNE1
KCNE2
SCN5A
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
I:3
I:4
I:1
47
I:2
75
2
II:1
?
78
?
III:3
III:12
III:4 III:11
II:2
II:7
?
III:5
III:10
III:9
?
?
III:6
III:7
II:8
?
III:13
II:3
II:4
66
III:1
?
II:9
II:5
II:6
67
70's
III:2
III:8
44
38
43
8
IV:13
IV:12
IV:10 IV:11
IV:9
IV:8
IV:6
IV:7
IV:2
IV:1
19
V:6
V:7
V:5
V:4
V:1
IV:3
IV:14
IV:5
IV:4
16
V:2
6
V:3
•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
Rory Collins (lead)
Cancer and learning
disability
ELSI and health
economics
Hugh Watkins (lead)
Ed Blair
Robert Clarke
Ian Tomlinson (lead)
Mike Parker (lead)
Anneke Seller
Alison Palmer
William Chambers
Tom Barclay
Kate Thomson
Sarah Parish
Asa Hedman
Jane Kaye
Karen Livesey
Ben Honey
Amy Silver
Cassie Fraser-Jones
Angela Jones
Andrew Smart
Christina Honeywell
Sam Knight
Sarah Wordsworth
Regina Regan
Kim Smith
Management
Jan Duff
Jenny Taylor
Andrew Wilkie