The Deciphering Development Disorders (DDD) project: What a genomic approach can achieve

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1 The Deciphering Development Disorders (DDD) project: What a genomic approach can achieve RCP ADVANCED MEDICINE, LONDON FEB 5 TH 2018 HELEN FIRTH DM FRCP DCH, SANGER INSTITUTE

2 3,000,000,000 bases in each human genome Disease & developmental disorders Health & development Fascinating facts about your genome! ~20,000 protein-coding genes ~30% of genes have a known role in disease or developmental disorders ~10,000 protein altering variants ~100 protein truncating variants ~70 de novo mutations (~1-2 coding ie. In exons of genes)

3 Rare Disease affects 1 in 17 people Prior to DDD, diagnostic success in patients with rare paediatric disease was poor Not possible to diagnose many patients with current methodology in routine use maximum benefit in this group DDD recruited patients with severe/extreme clinical features present from early childhood with high expectation of genetic basis Recruitment was primarily of trios (ie child and both parents) ~ 90% The Doctor Sir Luke Fildes (1887)

4 Making a genomic diagnosis of a rare disease improves care Accurate diagnosis is the cornerstone of good medical practice informing management, treatment, prognosis and prevention Enables risk to other family members to be determined enabling predictive testing with potential for surveillance and therapy in some disorders Reduces sense of isolation, enabling better access to support and information Curtails the diagnostic odyssey Not just a descriptive label; identifies the fundamental cause of disease February 28 th 2018

5 A genomic diagnosis can be a gateway to better treatment Not just a descriptive label; identifies the fundamental cause of disease Biallelic mutations in the CFTR gene cause Cystic Fibrosis CFTR protein is an epithelial ion channel regulating absorption/ secretion of salt and water in the lung, sweat glands, pancreas & GI tract. Ivacaftor is small molecule designed to potentiate opening of CFTR ion channel in patients with G551D mutation Changes from Baseline through Week 48 in Sweat Chloride & FEV1 According to Study Group. Ramsey et al. N Engl J Med 2011;365: Ivacaftor

6 4,000,000-5,000,000 variants in each genome* *The 1000 genomes Project Consortium. A global reference for human genetic variation. Nature 2015;526:68-74

7 Finding the causal variant Finding exceptions & integrating genotype & phenotype data to determine the consequences of variants for health and disease

8 The DDD study Aims: 1. Diagnosis - Transforming the diagnosis of rare disease in the NHS 2. Discovery - Discovering the genomic architecture of rare disease Partnership: NHS Genetic service throughout the UK Wellcome Sanger Institute Jointly funded by DH and Wellcome Collaboration: >40,000 DNA samples from ~13,500 UK families with a young family member affected by a rare disease where it had not been possible to identify a diagnosis using NHS testing.

9 DDD study: project delivery Project delivery (enabled by DECIPHER): ~200 Consultant Clinical Geneticists (NHS) ~100 Clinical laboratory scientists (NHS) ~50 Genetic counsellors and research nurses (NHS) ~20 scientists and bioinformaticians in the core team (Sanger) 6 members of the management committee (clinicians, scientists & an ethicist)

10 The DDD study Data generation: 33,500 exomes sequenced 10,000 trios (child + both parents) 3,500 singletons Sequence all 20,000 genes Sequence all 20,000 genes Sequence all 20,000 genes Data analysis: 1. Clinical - reporting against a panel of known developmental disorder genes (~1,450) with candidate diagnostic variants communicated to the genetics service for clinical & laboratory validation. 2. Research analyses focus on identifying new causes of developmental disorders by looking at genes with an excess of mutations in patients sharing similar clinical features

11 DECIPHER: Informatics platform supporting DDD study Highlights Flexible and responsible data sharing HPO Phenotype-linked Sequence and Copy- Number Variants ~25,000+ linked-anonymous records shared openly / >44,000 shared in consortia Direct depositor and DECIPHERmediated matchmaking support with >2,000 contacts since Oct countries/240+ Projects/1500+ registered users Real-time analysis and comparison tools More than 1400 publications resulting from matchmaking in DECIPHER Primary Objective To facilitate identification and interpretation of phenotypelinked genetic variation in rare disorders

12 DDD study - Entering phenotype

13 DDD study Data analysis

14 Diagnosis: Filtering data to make a genomic diagnosis 20,000 variants in genes Annotation required 400 rare & functional in relevant disease genes 1-2 with relevant inheritance 0-1 diagnoses Curated list of genes and diseases required Parental DNA sequence required Clinical review

15 Genes causing Rare Disease are scattered through our genome Complexity of rare disease needs comprehensive, flexible and scalable resources Detailed phenotype is essential for variant interpretation Many rare variants are novel Finding other patients with variants in the same gene & comparing their clinical features (phenotypes) is essential for diagnosis & discovery Fig. 5 Genetic diagnoses associated with broad phenotype categories Wright CF et al. Genetic diagnosis of developmental disorders in the DDD study. Lancet 2015;385:

16 Diagnosis & Discovery: Early outcomes of the DDD study Sequencing of >33,500 individuals (including 10,000 trios) >200 Complementary Analysis Proposals (CAPs) Diagnoses for > one third of children recruited to the study >1000 children have received diagnoses as a result of gene discovery in the DDD project

17 Diagnosis & Discovery: DDD Publications Nearly 100 peer-reviewed publications Flagship publications by whole collaboration Papers describing clinical features associated with individual genes led by clinicians in regional genetics services Leaflets for families written in conjunction with Unique (patient support group for rare genetic disorders)

18 Diagnosis & Discovery: Example - PURA syndrome Gene discovered in 2014 (3 of 4 patients were in DDD study) PURA Syndrome Foundation established 2015 and now has members around the world Further papers detailing clinical features Unique leaflet published 2015 Third annual conference being held in June 2018 Mutation within the 3 o structure of PURA

19 Diagnosis & Discovery: Building the DDD legacy Global sharing of knowledge gained via DECIPHER Discovery of >30 new genes for developmental disorders Generating data to estimate that developmental disorders caused by de novo mutations have an average prevalence of 1 in 300 births, depending on parental age. ~100 publications, with 2 flagship publications in Nature

20 Iterative reporting HYPOTHESIS: evidence-based analytical improvements will increase diagnostic yield

21 Iterative reporting: first 1133 trios Data from 2014 re-analysed, re-filtered and re-reported using 2017 pipeline All reported variants reviewed DDD clinical team & referring clinician Pathogenicity & contribution to phenotype Probands split into: DIAGNOSED = pathogenic/likely pathogenic variant and/or full/partial contribution to phenotype UNDIAGNOSED = uncertain/likely benign/benign variant or no contribution to phenotype

22 Improved diagnostic yield 28% in % in 2017

23 Improved diagnostic yield Wright CF et al. Making new genetic diagnoses with old data: iterative reanalysis and reporting from genome-wide data in 1,133 families with developmental disorders. GIM on line 11 Jan 2018

24 Innovative data sharing to improve discovery & diagnosis Between 23 NHS genetics services Solving one-offs - research variant track Managed data access for researchers working on developmental disorders In the scientific literature ~100 publications to date Globally via DECIPHER

25 Building knowledge and ensuring safe practice through the NHS Consortium A distributed network of expertise Genetic services see many instructive patients who can give important insights into genetic basis of disease Improve quality & safety of variant interpretation Increase knowledge of new disorders rapidly Increase opportunity for patients with Rare disease to participate in research & clinical trials by making them discoverable through open sharing in DECIPHER

26 Engaging clinical teams

27 Working with support groups

28 Making translation work in practice The DDD study, for my family, has been a bright light for us, amidst the fog of uncertainty. This information has been extremely helpful for us Helix Bridge, Marina Bay, Singapore

29 Rare patients & rare variants benefit from global collaboration Comprehensive sequence (SNVs) & structural variation (CNVs), nuclear & mitochondrial genome Dynamic real-time representation of genomic variation Flexible editable patient & variant entry & customisable browser Data-aggregation - Sharing findings from genetic services & DDD study to improve safety & quality of diagnosis for patients Global - >240 projects worldwide, finding new diagnoses for patients by matchmaking Data-sharing Potential to share data to improve health care globally, where patients wish

30 Acknowledgements DDD / Wellcome Sanger Institute Helen Firth, David FitzPatrick, Caroline Wright, Matt Hurles, Jeff Barrett, Michael Parker UK Clinical Genetics Community Patients & families