Rare Disease Research and the UK 100,000 Genome Project

Transcription

1 Rare Disease Research and the UK 100,000 Genome Project Prof F Lucy Raymond MA DPhil FRCP Department of Medical Genetics University of Cambridge UK Flr24@cam.ac.uk Copenhagen October

2 Precision Medicine Finding the right diagnosis Identifying the right treatment Minimising the side effects and maximising the benefit The alternative is imprecision medicine

3 Genomic Medicine Strategy Select technology that will maximise yield and long term utility of the data Select phenotype where genomic information has maximum predictive value for a disease or disease state or treatment

4 Genomic Medicine Strategy Select technology Genomes that will maximise yield and long term utility of the data Select phenotype Rare Diseases and Cancer where genomic information has maximum predictive value for a disease or disease state or treatment

5 England = 54 million Scotland = 5 million Wales = 3 million N Ireland = 2 million National Cohort Studies Regional Genetic Centres serving 5-6 million population Each centred around academic teaching Hospitals State health care and universities Clinician Scientist

6 Nature Genetics (2009) 68% 19% 13% AJHG (2010) 250 samples from families 19 novel genes ~1% genes on X redundant >100 genes on the X cause ID Sample number is critical DLG3 AP1S2 CUL4B ZDHHC9 BRWD3 UPF3B SLC9A6 MED12 IQSEC PTCHD1 USP9X CASK SYP NSDHL ZNF711 WDR13 FAAH2 GSPT2 HUWE1 FRMD7 PCDH19

7 10K individuals 4K whole genome sequence low resolution to identify rare variants absent from1000 genome project (ALSPAC and Twins UK cohorts) 6K whole exome sequence of cases 3000 severe obesity; 2000 neuropsychiatric disorders schizophrenia, autism; 1000 rare diseases: coloboma, ciliopathy, thyroid, neuromuscular, insulin resistance, hypercholesterolaemia, CHD and ID. Large scale replication study of 1200 cases and controls for a limited list of 1000 genes 2010

8 14K individuals with disease and their parents 4K exome trio sequences Developmental delay without a diagnosis 4000 trio completed so far Yield of ~35% in known genes 2011

9 10K individuals Large scale industrial and automated Minimal processing PCR free thus dosage calling possible Cost per genome / WES WGS for each specific project 13 projects 2012

10 Retinal Dystrophies 650 individuals 2012

11 Sequencing platform Exome or Genome? ARX Exome Genome 30 X coverage

12 Better for high and low GC content Carss et al submitted

13 Combined CNV and SNV Carss et al under review

14 Define deletion boundaries Carss et al under review

15 Complex rearrangements Retinal Dystrophy Diagnostic yield of 56% in 650 individuals Carss et al under review

16 Diagnostic yield Carss et al (2016) under review

17 >400 patients have answers to the cause of disease Consent to recall for additional studies Clinical trials for gene therapy or specific therapeutics based on genotype or phenotype Retinal Dystrophies

18 Paediatric Neurology Plasm a Urine DNA CSF DNA 2012

19 Trio or singletons De novo mutations are easily identified by trio analysis Parental DNA invaluable in interpreting the child s genome and provides a population sample for common disease assessment in longitudinal studies ~25% of children in the UK are from single parent households For diseases caused by haploinsufficiency large numbers of singleton affected cases has the power to detect novel genes whilst trio may be insufficient given the same number of

20 Mutations in KMT2B cause severe childhood onset dystonia Meyer et al, Nature Genet 2016 (in press)

21 Treatment trials : No response to standard anti-tonal agents Trihexyphenidyl Benzodiazepines Tetrabenazine Gabapentin Baclofen Meyer et al, under review 2016

22 Treatment trials: Deep brain stimulation Meyer et al, Nature Genet 2016 (in press)

23 100K individuals WGS 60K Rare Diseases 40K Cancer (Germline and Somatic) Translation into NHS services 2014

24 Genomic Medicine Centres 100K Genome Project deliver through 13 centres who recruit, deliver samples to a central hub and phenotypic data and analyse and confirm results from the hub Procure large scale sequencing capacity centrally to ensure cost effective production, standardised quality, time efficiency, central access and deposition of data to maximise utility But loss of flexibility and reactivity of production development

25 Consent Research consent but NHS diagnostic pipeline quality Genome sequence Pertinent finds are returned back to the patient in a clinical context Opt in to incidental findings Data mining now and in perpetuity using health care records Consent to be re-contacted for future studies

26 Data Genome sequence performed in UK Data protection of personal identifiable data of the highest priority Genomic and health care data will be used by industry Use of the data agreed not to identify individuals taking part Genomic data stored in a central place in an embassy, use of the data for the benefit of interpretation of data for others Parental data will be used to interpret genomes of affected children but also for health analysis of

27 Data collection ~200 disease areas/conditions so far Each have their own set of standardised HPO Human Phenotype Ontology terms as key features and each patient scored against this Information about previous genetic testing Additional laboratory tests Centralised data stored via electronic national health records

28 Data ownership Genomics England is wholly owned by the Department of Health Although data is owned Genomics England patients have the right to ask for their data Data access is the main concern of the research community but ownership is less so long as they can publish and make use of the data Collaborations and data access from outside the UK

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30 Participants Recruited Recruitment per site Rare Disease CUH recruitmen t CUH revised traj NUH recruitmen t NUH revised traj UHL recruitmen t

31 Cardiovascular disorders 54 Dermatological disorders 8 Dysmorphic and congenital abnormality syndromes 2 Endocrine disorders 6 Growth disorders 2 Haematological disorders 1 Hearing and ear disorders 7 Neurology and neurodevelopmental disorders - non ID 40 Neurology and neurodevelopmental disorders - ID 63 Ophthalmological disorders 8 Embedding into NHS services Renal and urinary tract disorders 18 Respiratory disorders 2 Rheumatological disorders 1 Skeletal disorders 1 Tumour syndromes 1 Ultra-rare disorders 16 SUM 238

32 Data so far Early days 13,000 genomes sequenced Results on the pilot phase emerging Initially screen virtual panels of known genes for a specific disorder to confirm and deliver to patients within the NHS health care system If negative then referred onto the research community for further analysis to identify new genes of novel

33 Genomic Precision Medicine Finding the right diagnosis where the genome is a high predictor of disease Identifying the right treatment by genome driven clinical trials Minimising the side effects and maximising the benefit

34 Acknowledgements Department of Medical Genetics, University of Cambridge, UK Detelina Grozeva Keren Carss Annabel Whibley Olivera Spasic-Boskovic Kate Baker Institute of Child Health, UCL Manju Kurian Esther Mayer Amy McTague Joanne Ng Sanger Institute, Cambridge Matthew Hurles James Floyd East of England Genomics Medicine Centre Karola Rohnstrom Emily Li GOLD Consortium UK10K Consortium DDD study NIHR Bioresource-Rare Diseases Willem Ouwehand Alba Sanchis-Juan Eleanor Dewhurst Marie Erwood