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Www.iccg.org A Unified Clinical Genomics Database NHGRI - U41 Genomic Resource Grant.

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Presentation on theme: "Www.iccg.org A Unified Clinical Genomics Database NHGRI - U41 Genomic Resource Grant."— Presentation transcript:

1 A Unified Clinical Genomics Database NHGRI - U41 Genomic Resource Grant

2 Variant Analysis for General Genome Report 3-5 million variants ~20,000 Coding/Splice Variants “Pathogenic” Variants Published as Disease-Causing Genes 5-10 Variants Pharmacogenetics <1% Rare CDS/Splice Variants LOF in Disease Associated Genes Variants Review evidence for gene-disease association and LOF role Review evidence for variant pathogenicity

3 Classification of Reported Pathogenic Variants found in Human Genomes Benign 18% Likely Benign 26% Uncertain significance – 52% Pathogenic – 2% Likely Path – 1%

4 U41 Genomic Resource Grant: A Unified Clinical Genomics Database To raise the quality of patient care by: Standardizing the annotation and interpretation of genomic variants Sharing variant and case level data through a centralized database for clinical and research use Implementing an evidence-based expert consensus process for curating genes and variant interpretations

5 Supporting data collection, submission and curation Work with NCBI to design ClinVar to meet the needs of the community Develop data dictionary, ontologies, and work with standards bodies Define data submission and access policies for variant and case-level data including genotypes and phenotypes Work with labs to solicit and support data submission Evidence-based curation of structural variants - (Riggs et al ) Evidence-based curation of sequence variants (ACMG Committee work in progress) Develop a gene-centric resource to define the medical exome and provide tools to support use in genomic medicine Work with vendors to improve reagents for genomic analysis (CMA, WES, WGS)

6 NIH NCBI ClinVar

7 ClinVar SubmittersVariantsGenes OMIM Harvard Medical School and Partners Healthcare InVitae Inc International Standards For Cytogenomic Arrays GeneReviews ARUP Laboratories LabCorp Sharing Clinical Reports Project 9022 Finland Institute for Molecular Medicine Tuberous Sclerosis Database 4311 ClinSeq Project Leiden Muscular Dystrophy Database GeneDx 2053 Emory Genetics Laboratory 4813 American College of Medical Genetics and Genomics 231 Osteogenesis Imperfecta Database; University of Leicester 153 Ambry Genetics 101 Other laboratories (19) 5225 Total

8 Sequencing Laboratories Which Have Agreed to Share Data Alfred I Dupont Hospital for Children All Children's Hospital St. Petersburg Ambry Laboratories ARUP Athena Diagnostics Baylor Medical Genetic Laboratories Boston Children's Hospital Boston University Children's Hospital of Philadelphia Children's Mercy Hospital, Kansas City Cincinnati Children's Hospital City of Hope Molecular Diagnostic Lab CureCMD Denver Genetic Laboratories Detroit Medical Center Emory University Fullerton Genetics Laboratory GeneDx Cleveland Clinic Greenwood Genetics Harvard-Partners Lab for Molec. Medicine Henry Ford Hospital Huntington Medical Research Institutes Illumina Clinical Services Lab Indiana University/Perdue University InSiGHT LabCorp / Integrated Genetics / Correlagen Masonic Medical Research Laboratory Mayo Clinic Mt. Sinai School of Medicine Nationwide Children's Hospital Nemours Biomolecular Core, Jefferson Medical Oregon Health Sciences University Providence Sacred Heart Medical Center Quest Diagnostics SickKids Molecular Genetic Laboratory Transgenomics University of Chicago University of Michigan University of Nebraska Medical Center University of Oklahoma University of Penn University of Sydney University of Washington Women and Children's Hospital Wayne State University School of Medicine Yale University

9 Documenting arguments will improve the evidence-based assessment of variants

10 53 discrepancies: 60% differ based upon likelihood (Benign vs LB, P vs LP) 34% differed VUS vs Likely Pathogenic/Likely Benign 6% differed VUS vs Pathogenic 20% discrepant U41/ClinVar pilot project ScopeNumber of alleles Total submitted to ClinVar997 Multiple assertions269 Comparison of three laboratories classifications for variants in 12 RASopathy genes: BRAF, CBL, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, PTPN11, RAF1, SHOC2, SOS1, SPRED1

11 84% differences were Lab A reporting a more aggressive assertion (Pathogenic/Benign) than Lab B/C (LP, LB, VUS) 16% of differences were Labs B/C reporting a more aggressive assertion than Lab A Lab Classification Differences

12 ACMG Lab QA Committee on the Interpretation of Sequence Variants ACMG Sue Richards (chair), Heidi Rehm (co-chair) Sherri Bale, David Bick, Soma Das, Wayne Grody, Madhuri Hegde, Elaine Spector AMP Julie Gastier-Foster, Elaine Lyon CAP Nazneen Aziz, Karl Voelkerding 12

13 5 Categories: Pathogenic Likely Pathogenic Uncertain significance Likely benign Benign Pathogenic = 1 stand-alone OR 2 strong OR 1 strong + ≥3 supporting Likely Pathogenic = 1 strong + 2 supporting OR ≥4 supporting Benign = 1 stand-alone OR 2 strong OR 1 strong + ≥3 supporting Likely benign = 1 strong + 2 supporting OR ≥4 supporting

14 *Variants should be classified as Uncertain Significance if other criteria are unmet

15 Large variant datasets Intra-laboratory Evidence-based review Practice guidelines Expert Curation Single-Source Curation Uncurated Multi-Source Curation Guideline Inter-laboratory dbSNP/dbVar ClinVar QC and Expert Concensus

16 Curation - ClinVar

17 Analysis of LOF Variants - single genome Pathogenic - 2 VUS – 1 (novel) Excluded 46 Novel/Rare - 41 Common 33 8 Reported Rare LOFs (Both AR 1 novel 1 known) False Positives 13 Not Mendelian 14 LOF not a disease Mechanism LOF variants below 5% MAF from one case Update database

18 1.Define genes with medical relevance 2.Technical challenges High GC Pseudogenes/homologies Repeat expansions Common sites of structural variation 3.Variant types (denote common vs rare types) Sequence variants (substitutions, small indels) Loss-of-function vs. Gain-of-function CNV – haploinsufficient vs. triplosensitive Other structural changes (translocations, inversions, etc) Imprinted loci Repeat expansions 4.Medically relevant transcripts 5.Gene regions of pathogenic relevance 6.Patterns of inheritance (dominant, recessive, X-linked, mitochondrial, de novo, etc) 7.Phenotypes and evidence base for phenotype associations 8.Available approaches to define variant pathogenicity (assays, tools, etc) 9.Clinical utility measures 10.Clinical decision support opportunities Gene-centric resource Initiated through collaboration amongst CHOP, Emory, and Harvard/Partners and Structural Variant workgroup

19 U41 - Working with Existing Efforts NCBI (ClinVar, dbSNP, dbVar, dbGaP, GTR) and EBI NHGRI (CRVR, eMERGE, CSER, ROR), IRDiRC Regulatory and Standards: ACMG, CAP, CDC, FDA, ASHG, AMP, CMGS, Global Alliance Locus Specific Databases (LSDBs – LOVD and non-LOVD) InSiGHT, PharmGKB, MSeqDB, CFTR2, ENIGMA, etc Human Variome Project and HGVS PhenoDB (Ada Hamosh) and Human Phenotype Ontology (Peter Robinson) OMIM (Ada Hamosh) and GeneReviews (Bonnie Pagon) Patient Advocacy Groups (Genetic Alliance, Patient CrossRoads, UNIQUE, Disease Specific Groups) Industry partners (reagents, instruments, software, etc)

20 ClinGen: The Clinical Genome Resource Program Collaboration between: NHGRI U41 Grant – PIs: Ledbetter (Geisinger), Martin (Geisinger), Nussbaum (UCSF), Mitchell (Utah), Rehm (Partners/Harvard) NHGRI U01 “Clinically Relevant Variant Resource” Grants – Grant 1 PIs: Bustamante (Stanford), Plon (Baylor) – Grant 2 PIs: Berg (UNC), Ledbetter (Geisinger), Watson (ACMG) NCBI – ClinVar

21 U41 UNC Geisinger ACMG U01 Stanford Baylor U01 ClinGen Delegation of Responsibilities

22 CoreDB Disease Area Curation Tool ClinGen System Interactions OMIM Patient Registries EHR Interface Expert Curation of Genes and Variants by Clinical Domain and Disease Area Workgroups dbGaP LSDBs Labs (Genotypes & Phenotypes) Gene Resource (Medical Exome, Actionability) CNV Curation Tool (JIRA) Application Interface External Informatics Activities Enabled Expert Curated Variants Case-level Data Variant-level Data ClinVar Disease WGs Clinical Domain WGs Data Crowd- sourced Curation Controlled Access Public Access Private Pharm GKB Machine Learning Algorithms Population Datasets Medical Lit Portal for the Public

23 International Collaboration for Clinical Genomics – Over 190 institutional members – Over 2800 individual members Annual Conference June 10-12, 2014, Bethesda, MD – Attendees include laboratory directors, physicians, genetic counselors, researchers, parents, government employees, regulatory agency representatives, and vendor partners

24 Bioinformatics and IT Workgroup Karen Eilbeck (co-chair) and Sandy Aronson (co-chair) ARUP: Brendon O’Fallon; Cartagenia: Steven Van Vooren; Emory: Stuart Tinker; GeneDx: Rhonda Brandon, Lisa Vincent; Mayo: Eric Klee; NCBI: Deanna Church, Jennifer Lee, Donna Maglott; George Riley; Partners Healthcare: Eugene Clark, Larry Babb, Matt Varugheese; University of Chicago Teja Nelakuditi; Utah: Karen Eilbeck, Shawn Rynearson Bioinformatics and IT Workgroup Karen Eilbeck (co-chair) and Sandy Aronson (co-chair) ARUP: Brendon O’Fallon; Cartagenia: Steven Van Vooren; Emory: Stuart Tinker; GeneDx: Rhonda Brandon, Lisa Vincent; Mayo: Eric Klee; NCBI: Deanna Church, Jennifer Lee, Donna Maglott; George Riley; Partners Healthcare: Eugene Clark, Larry Babb, Matt Varugheese; University of Chicago Teja Nelakuditi; Utah: Karen Eilbeck, Shawn Rynearson Sequence Variant Workgroup Madhuri Hegde (co-chair, Emory) Sherri Bale (co-chair, GeneDx) Carlos Bustamante (Stanford) Soma Das (U Chicago) Matt Ferber (Mayo) Birgit Funke (Harvard/MGH) Marc Greenblat (UVM) Elaine Lyon (ARUP) Dona Maglott (NCBI) Sharon Plon (Baylor) Heidi Rehm (Harvard/Partners) Avni Santani (CHOP) Patrick Willems (Gendia) Sequence Variant Workgroup Madhuri Hegde (co-chair, Emory) Sherri Bale (co-chair, GeneDx) Carlos Bustamante (Stanford) Soma Das (U Chicago) Matt Ferber (Mayo) Birgit Funke (Harvard/MGH) Marc Greenblat (UVM) Elaine Lyon (ARUP) Dona Maglott (NCBI) Sharon Plon (Baylor) Heidi Rehm (Harvard/Partners) Avni Santani (CHOP) Patrick Willems (Gendia) Structural Variant Workgroup Erik Thorland (co-chair, Mayo) Swaroop Aradhya (co-chair, InVitae) Deanna Church (NCBI) Hutton Kearney (Fullerton) Charles Lee (Jackson Labs) Christa Martin (Emory) Sarah South (ARUP) Chad Shaw (Baylor) Karin Wain (Utah) Structural Variant Workgroup Erik Thorland (co-chair, Mayo) Swaroop Aradhya (co-chair, InVitae) Deanna Church (NCBI) Hutton Kearney (Fullerton) Charles Lee (Jackson Labs) Christa Martin (Emory) Sarah South (ARUP) Chad Shaw (Baylor) Karin Wain (Utah) Phenotyping Workgroup David Miller (chair, Harvard) Ada Hamosh (Hopkins) Karen Eilbeck (Utah) Monica Giovanni (Geisinger) Robert Green (Harvard/BWH) Mike Murray (Geisinger) Robert Nussbaum (USCF) Erin Riggs (Emory) Peter Robinson (Berlin) Steven Van Vooren (Cartagenia) Patrick Willems (Gendia) Phenotyping Workgroup David Miller (chair, Harvard) Ada Hamosh (Hopkins) Karen Eilbeck (Utah) Monica Giovanni (Geisinger) Robert Green (Harvard/BWH) Mike Murray (Geisinger) Robert Nussbaum (USCF) Erin Riggs (Emory) Peter Robinson (Berlin) Steven Van Vooren (Cartagenia) Patrick Willems (Gendia) Engagement, Education and Access Workgroup Andy Faucett (chair, Geisinger) Erin Riggs (Emory) Danielle Metterville (Partners) Genetic Counselors from participating laboratories Engagement, Education and Access Workgroup Andy Faucett (chair, Geisinger) Erin Riggs (Emory) Danielle Metterville (Partners) Genetic Counselors from participating laboratories Consultants Les Biesecker, Johan den Dunnen, Robert Green, Ada Hamosh, Laird Jackson, Stephen Kingsmore, Jim Ostell, Sue Richards, Peter Robinson, Lisa Salberg, Joan Scott, Sharon Terry Consultants Les Biesecker, Johan den Dunnen, Robert Green, Ada Hamosh, Laird Jackson, Stephen Kingsmore, Jim Ostell, Sue Richards, Peter Robinson, Lisa Salberg, Joan Scott, Sharon Terry U41 Principal Investigators and Workgroups NIH U41 PIs: David Ledbetter (Geisinger), Christa Martin (Geisinger), Joyce Mitchell (Utah), Robert Nussbaum (UCSF), Heidi Rehm (Harvard)

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