100,000 Genomes Project Rare Disease Programme. Dr Richard Scott Clinical Lead for Rare Disease, Genomics England

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1 100,000 Genomes Project Rare Disease Programme Dr Richard Scott Clinical Lead for Rare Disease, Genomics England

2 Recruitment to 16 th June 31,231 rare disease participants Average = 490 participants / week Mean family size = July

3 Rare disease programme >200 recruitment categories Covering >3000 Rare Diseases Detailed standardised eligibility Prior genetic testing in line with current standard practice Core clinical data set: Disease status Pedigree data Human Phenotyping Ontology Clinical test data where relevant and not captured by HPO Using established standards wherever possible 10/07/ July

4 Interpretation pipeline DNA Patient/ family Phenotypes & Pedigree Clinical assessment Validation Outcomes GeCIP(s) Gene Panels Report QC Reporting tool Genome sequence Annotated VCFs Gene Panel Variant filtering Tiered variants Review Annotation Companies

5 Interpretation pipeline DNA Patient/ family Phenotypes & Pedigree Clinical assessment Validation Outcomes GeCIP(s) Gene Panels Report QC Reporting tool Genome sequence Annotated VCFs Gene Panel Variant filtering Tiered variants Review Annotation Companies

6 Interpretation pipeline DNA Patient/ family Phenotypes & Pedigree Clinical assessment Validation Outcomes GeCIP(s) Genome sequence Annotated VCFs Gene Panels Gene Panel Variant filtering Tiered variants Report QC Review Reporting tool Annotation Companies

7 Pre-interpretation sign-off PanelAssigner 10 July

8 PanelApp

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10 Interpretation pipeline DNA Patient/ family Phenotypes & Pedigree Clinical assessment Validation Outcomes GeCIP(s) Test request Report QC Reporting tool Genome sequence Annotated VCFs Gene Panel Variant filtering Tiered variants Review Annotation Companies

11 Tiering 10 July

12 Interpretation at the hospitals Tier 1 Tier 2 Tier 3 Singletons Duos Trios Larger Tiering Automated focused initial analysis set up prior to interpretation Aims to mirror standard diagnostic analysis Tier 1 or 2' variants in 0-5 genes within prescribed panel(s) Non-penetrance pipeline can be run 2. Broader analysis CIP software allows hospitals further, bespoke analysis Tier 3 standard GeL pipeline but not restricted to gene panels; s variants Other tools, dependent on which CIP system 3. Lab-clinical team curate variants and record outcomes Curations are saved in the central knowledge base Record clinical impacts of diagnostic result 10 July

13 From Tiering to MDT Guide to Clinical Reporting for Rare Disease, June July

14 From Tiering to MDT Interpretation Request and Interpreted Genome JSON files Accessible to NHS GMCs via CIP API Guide to Clinical Reporting for Rare Disease, June July

15 From Tiering to MDT Lists pending/open/closed cases Links to CIP page for family Collects outcomes Access to HTML reports (incl coverage) & other files Guide to Clinical Reporting for Rare Disease, June July

16 Semi-automated Interpretation pipeline DATA DISTRIBUTION FRAMEWORK DNA Patient/ family Phenotypes & Pedigree Clinical assessment Validation Outcomes GeCIP(s) Genome sequence WORKFLOW MANAGER Annotated VCFs Gene Test request Panels Gene Panel Variant filtering Tiered variants Report QA Review Reporting tool Annotation Companies

17 Return of results to sites Reports to date (to 19 th June) 1988 families (4106 genomes) dispatched to CIPs 1741 families (3462 genomes) reports sent to GMCs 221 families (467 genomes) outcomes questionnaires completed by GMC labs Includes >85% of pilot; status summary to sites for remaining in coming week Upcoming Further batch passing through pipeline now >1000 families = ALL of the families with HPO data and no other data issues on GRCh37 Release to CIPs from mid-july Results to GMCs from 1-2 weeks after that (i.e. from late July) Next steps Move to GRCh38 reporting (and with it, CNV calls that we expect to use) Move away from batches to even out flow Looking at mechanisms to allow GMCs greater control re flow 10 July

18 A pipeline for diagnostics Validation, QA and accreditation Major focus of the next year will be validation, QA and accreditation This will involve analysis of samples already held as part of the programme Plus sequencing of additional positive control samples Existing pipeline components New components, eg STR

19 Summary An overview of the project s approach to reporting in RD An introduction to some of the components that are available to NHS GMCs Including PanelApp, CIP API and Interpretation portal Increased automation is beginning to increase the pace at which reports can be returned to sites Upcoming batch of >1000 main programme families Next steps including Move to build 38 Focus of experimental activity to validate pipeline 10 July

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