1. Understanding how genomics will transform the NHS
Over the Next Decade
The 100,000 Whole Genomes Project
Prof Mark Caulfield FRCP FMedSci,
Chief Scientist
T
William Harvey Research Institute
Barts NIHR Cardiovascular Biomedical Research Unit
Queen Mary University of London

2. Genomics England- mission
• 100,000 whole genome sequences in NHS
patients with rare inherited disease, cancers
and pathogens from the NHS in England
• Whole Genome Sequencing
• Generate health and wealth
• Legacy of infrastructure, human capacity and
capability
• World-leaders in the application of Genomic
Medicine for healthcare

3. Rare Inherited Disease

4. Rare inherited diseases
• <5% of the population or about 5/10,000 people
• 3 million people in the UK
• 7000 rare disorders- often disabling, shorten life,
costly
• Working on 110 disorders
• Detailed patient characterisation
• Human Phenotype Ontology & progression
• Rare Disease Registry
• WGS 30x increases discovery by about 25-30%

5. 23/03/2015 https://decipher.sanger.ac.uk 5
France
Germany
Global Electronic Linkage to diagnose rare disease

6. Rare Disease Pilot- first diagnoses
Newcastle – Centre for Life

7. Two brothers: distal sensory-motor neuropathy
Two brothers with a distal
motor neuropathy
Symptoms began in late
40s-early 50s progressed
over 20-25 years
Currently aged 79 and 72
Remain ambulatory but
with significant difficulties
Whole Genome Sequence
Expected pathogenic mutation in a transport gene for Serine
Validation: Confirmed
Opportunity: Potential for treatment trial with l-serine

8. Diagnostic Odyssey
Additional
investigations
Nerve conduction
studies (x 4) - £1600
Total cost: £2905 (excluding routine biochemical investigations)
In 3 years patients will have WGS routinely
In 10 years -better ideas of prognosis
Maybe in some not all we’ll be developing new medicines

9. Father and daughter: focal segmental glomerulosclerosis
- Father presented in late 20s with
hypertension and proteinuria
- Dialysis aged 29, renal transplant aged 30.
- Transplant failed aged 55
- Re-transplanted aged 57 last year
- Both his father, brother and uncle died from
the same condition
- His daughter is also displaying features of
proteinuria.
- She has worried for years her daughter may
have inherited this kidney problem
Ο
Pathogenic mutation: INF2, c.653G>A, p.R218Q
Sanger: Confirmed in both affected patients
Previously described pathogenic mutation

10. PCSK9 and cholesterol lowering
• Gain-of-function mutation in PCSK9 in Familial
Hypercholesterolaemia (1 in 500) with increased CAD.
• Injectable monoclonal antibody in I and II studies in FH
41% to 58% reduction in LDL-C now in CV outcome trials
Cystic fibrosis- combination therapy
Combination of ivacaftor and
lumacaftor in ages 12 and
older homozygous for
ΔF508del.
Phase 3 trials - improved lung
function (FEV1 2.6 – 4%).

11. Cancer

12. Cancer
• Disease of disordered genomes – over 200 drivers known
• Drugs targets, Tumour heterogeneity, evolution of cancer,
Stratified medicine
• Lung, breast, colon, prostate, ovary and, Leukaemia and
• Rare and Childhood Cancers, unknown primary
• Sequential biopsy of recurrent cancer
• Stratified medicine- Focus 4
• Optimise Molecular Pathology
• WGS at 75x somatic and 30x germline
• International Cancer Genomes Consortium- the Cancer
Genome Atlas

13. BRAF inhibitors for Melanoma

14. Opportunity for stratified trials
• Combine sequence and Clinical Trials
• Enhanced patient enrolment
• Identify the right genotype and connect
clinical teams with companies/academics
• Identify important genetic predictors of
adverse effects
• Adaptive designs
• In 10 years more specific therapies
targeted to genetic make up of the cancer
and the patient

15. Lung cancer before and after Gefitinib
epidermal growth factor mutation

16. Pathogens

17. Pathogens
• Stratifying response, minimising adverse
events and tracking outbreaks
• M. Tuberculosis resistance and epidemiology
• Hepatitis C genotype selects therapy
• HIV –Treatment for life and resistance testing
is in the care pathway.
• Extreme human response to sepsis
• International linked datasetss

18. Implementing the programme

19. Genomics England – The main programme
NHS Genomic Medicine Centres
Rare diseases, cancers and pathogens
Broad consent, characteristics, molecular pathology and samples
MRC £24m Research Data Infrastructure (GeCIP)
Sequential builds of pseudonymised data and WGS
Safe haven- users work within
Refreshable identifiable
Clinical Data
Life-course registry
Linked to anonymised
Whole Genome SequenceSequencing Centre
Wellcome Trust £27m
DNA & multi-omics
Repository
Primary Care
Hospital episodes
Cancer Registries
Rare Disease
Registries
Infectious Disease
Mortality data
Patient entry
Annotation & QC
Scientists & SMEs
Product
comparison
Clinicians &
Academics
Industry
Training &
capacity
Fire wall
Patient data stays in safe haven
Only processed
results pass outside
Oxford
Big Data

20. Electronic Health Records
• High-quality, cutting-edge research linking electronic
health data
• Life course refreshable dataset
• Solve the challenges of multiple electronic records
• Paving the way for future cohort enrichment
• Build capacity in health informatics research.
• Continuous traits
• Outcomes research
• Multiple data-points for the same phenotype
• Enriched by trait specific registries.

21. Establishment Phase
• Illumina Partnership
• New NHS Sequencing Centre £27m
from Wellcome Trust
being built at the Sanger Centre
• 11 New NHS Genomic Medicine Centres in
England to enrol, validate and feedback to
patients
• £24m for the UK Data Infrastructure
• for Genomic Medicine
• 700 person years of Masters PhD and
short course training - £25m

22. Genomics England
Clinical Interpretation Partnership

23. Why do we need a Clinical Interpretation Partnership?
17 yrs ?3 yrs
Start 2014
The standard way The GeCIP way
Securing Patient Benefit

24. Organised in Disease Domains Key functions and outputs
UK led - steering group Appoint domain leader & sub-groups
Genomics England Chief Scientist’s Team Oversight, informatics and logistics for the
programme
Multiple phenotypic sub-groups Deeper phenotyping & extend programme
Functional characterisation
Multi-omics
Single cell or model functional studies
RNA, epigenetics, proteomics
Analysts and Bio-informaticians Novel analytic approaches
Interpretation - NHS and PHE teams and
Researchers
Highest fidelity dynamic reporting system
Integrated Multi-Disciplinary Team
Training - HEE/GECIP trainees Genomic Medicine Academy
Precompetitive industry partners Academic/Industry Collaboration
Genomics England Clinical Interpretation Partnership
Rare Disease, Cancer and Infection Domains

25. In 10 years- Genomics England
• 100,000 WGS on NHS patients and pathogens
• WGS deployed routinely- also in other diseases
• Harnessing electronic health records
• Patient reported outcomes and more remote
monitoring
• New diagnostics and therapies and opportunities for
patients
• By end of 2017

26. Genomics England – who are we?
• Officers: Sir John Chisholm (Executive Chair)
• Mark Caulfield (Chief Scientist), Nick Maltby
(Company Secretary), Jim Davies (Informatics), Viv
Parry (Outreach), Graham Colbert (COO)
• Board: Prof Dame Sally Davies (CMO), Kevin Dean
(Cisco), Prof Sir John Bell, Jon Symonds (Audit), Prof
Sir Malcom Grant (NHSE)
• Advisory Committees:
• Science: Sir John Bell, IT: Kevin Dean and Ethics: Mike
Parker

27. Team members
• Science- Tom Fowler, Jeanna Mahon-Pearson,
Laura Riley, Nora Wong, Clare Turnbull.
• Informatics - Jim Davies, Tim Hubbard,
Augusto Rendon, Matthew Parker, Andrew
Devereaux, Katherine Smith, David Brown

28. Thanks
Cambridge, UCLH, GOSH, Moorfields, Newcastle,
Manchester, Guys and St Thomas’s, Oxford,
Liverpool, Sheffield, Leeds, Birmingham, Royal
Marsden, Southampton, UK CLL Consortium,
CRUK, RCPath, NHSE, DoH, Biobank UK, Sanger,
EBI, KCL, UCL and QMUL