Arno G. Motulsky Endowed Chair Medicine and Genome Sciences - PowerPoint PPT Presentation

Gail P. Jarvik, M.D., Ph.D. Arno G. Motulsky Endowed Chair Medicine and Genome Sciences Professor and Head, Medical Genetics University of Washington, Seattle Challenges in the implementation of genomic medicine

Genomic Medicine Obstacles • Lack of practice guidelines / Lack of insurance coverage / reimbursement • Need for evidence base • When it helps • How best to do it • What do all those variants mean? • Regulatory climate / New legislation? • Lack of non-geneticist provider training • Patient/consent issues, family communication • Postmortem genome-sharing

Genomic medicine is another new technology § Study required to implement safely and effectively § Harm of implementing both too fast and too slowly § Need to evaluate best practices § Understand economics (and convince insurers) § We have learned that evidence trumps “logic” p Think hormone replacement therapy

CSER Ongoing Outcomes Efforts: Steps to access to genomic medicine Evidence Practice Insurance Research base Guidelines Coverage Next generation sequencing panels for the diagnosis of colorectal cancer and polyposis syndromes: a cost- J Clin Onc. effectiveness analysis. Gallego, Shirts, Bennette, et al. 2015. in press Genet Med. 2014. PMID: 25394171 Contemp Clin Trials. 2014. PMID: 24997220

Regence Insurance Policy 64 effective (7/1/14) § “The following genetic panels are considered investigational because the current scientific evidence is not yet sufficient to establish how test results from panels which include a broad number of genes may be used to direct treatment decisions and improve health outcomes associated with all components of the panels.” § List of ALL panels, including cystic fibrosis 32 mutation panel

Exomes can save money without changing management: a case • Patient in teens • Movement disorder early in life • Saw 12 experts in centers from Vancouver to Texas without a diagnosis • PE: choreoathetosis and dystonia of limbs, most prominent at rest; progressed to include facial twitches and mild dysarthria • Exome: de novo R418W (c.1252C>T) in ADCY5 • Familial Dyskinesia with Facial Myokymia • Ended diagnostic odyssey Chen et al, Annals of Neurology.

> 200 clinicians involved Explore, within an active clinical setting, the application of genomic sequence data to the care of patients. Twitter #hail_CSER

NHGRI’s Genomic Medicine Research Program Program Goal Σ $M Years Use biorepositories with EMRs and GWA data to eMERGE II 31.1 FY11-14 incorporate genomics into clinical research and care eMERGE- Apply PGRN’s validated VIP array for discovery and 9.0 FY12-14 PGx clinical care in ~9,000 patients Explore infrastructure, methods, and issues for CSER 66.5 FY12-16 integrating genomic sequence into clinical care Investigate whether/when/how to return individual RoR 5.7 FY11-13 research results to pts in genomic research studies Develop and disseminate consensus information on ClinGen 25.0 FY13-16 variants relevant for clinical care Develop and disseminate methods for incorporating IGNITE 32.3 FY13-16 patients’ genomic findings into their clinical care Explore possible uses of genomic sequence NSIGHT 10.0 FY13-16 information in the newborn period Diagnose rare and new diseases by expanding UDN 67.9 FY13-17 NIH’s Undiagnosed Diseases Program

CSER U Award Study Populations

Enrollment & Germline Findings More interactive data-sets available online at http://cser-consortium.org/impact

Diagnostic Yield Varies by CSER Study Population Cases Path/LP VUS Other Yield Cancer (Adult) 164 7 30 127 4% Cancer (Pediatric) 150 24 120 6 16% Dysmorphology 88 16 16 56 18% Heart Disease 117 27 44 46 23% Bilateral sensorineural hearing loss 34 8 12 14 24% Neurological Diagnosis 211 37 41 133 18% Retinal 55 18 13 24 33% Preconception (Carrier) 45 31 0 14 69%

UW Randomized control trial Comparing whole exome sequencing to usual care for adult patients having clinical genetic testing for hereditary colorectal cancer/polyps ~6 Weeks ~2 Months Clinic Visit 1 Clinic Visit 2 Research Visit (Baseline) (WES) (WES) Clinical CRCP Clinical and Discuss Genetic Clinic Clinic Visit Research Visit exome CRCP Incidental Counseling Visit 2 2 + 2 weeks Genetic Test Findings 3 Sets of + 2 weeks + 1 month + 1 month, Results Consent Surveys + 4 months, Discussion 2 Sets of 1 Set of +7 months, Surveys Surveys +10 months Clinic Visit 2 Research Visit Blood Draw (UC) (UC) Various surveys Randomize Clinical CRCP Review Family Genetic Test History Usual Results Care Exome N=220 over 3.5 years ~14 Months •

So many variants, so little time § Average persons WGS has >3.5 million variants from a reference sequence* § 0.6 million are rare or novel § 400 GENES have rare or novel, nonsynonymous (coding) variants in conserved regions § Guessing < 10K variants with well established pathogenic role § Need annotations! § Pathogenic, Likely pathogenic, VUS, Likely benign, benign * Kohane, Tsing, Kong, Genet Med 2012, PMID 22323072

Submitter Variants Genes Expert Consortia and Professional Organizations ClinVar International Society for Gastrointestinal Hereditary Tumours (InSiGHT) 2362 8 Clinical and Functional Translation of CFTR (CFTR2) 133 1 American College of Medical Genetics and Genomics (ACMG) 23 1 Clinical Laboratories National International Standards For Cytogenomic Arrays Consortium Laboratories 14441 >14000 Partners Healthcare Laboratory for Molecular Medicine 12133 222 University of Chicago Genetic Services Laboratory 7129 600 GeneDx 6757 574 Database Emory University Genetics Laboratory 5192 537 Ambry Genetics 4150 47 Sharing Clinical Reports Project for BRCA1 and BRCA2 2147 2 Laboratory Corporation of America (LabCorp) 1390 140 of variants ARUP Laboratories 1304 7 InVitae 1102 35 U. Washington CSER Program with Northwest Clinical Genomics Laboratory 625 76 University of Washington Collagen Diagnostic Laboratory 411 1 Children's National Medical Center GenMed Metabolism Laboratory 317 1 Pathway Genomics 166 17 Baylor College of Medicine Medical Genetics Laboratories 155 12 BluePrint Genetics 123 56 Counsyl 112 2 University of Pennsylvania School of Medicine Genetic Diagnostic Laboratory 68 1 Research Programs and Locus-Specific Databases http://www.clinvar.com/ Breast Cancer Information Core (BIC) 3734 2 1381 10 Royal Brompton Hospital Cardiovascular Biomedical Research Unit Muilu Laboratory, Institute for Molecular Medicine Finland 840 41 ClinSeq Project, National Human Genome Research Institute, NIH 425 36 Lifton Laboratory, Yale University 389 279 Total unique variant submissions to ClinVar with PALB2 Leiden Open Variation Database 242 2 Dept of Ophthalmology and Visual Sciences, Kyoto University Hospital 171 59 clinical assertions = 76606 (Jan 20, 2015) Dept Zoology, M.V. Muthiah Government College, India 58 3 Aggregate Databases http://www.ncbi.nlm.nih.gov/clinvar/submitters/ 24973 Online Mendelian Inheritance in Man (OMIM) 3606 4035 GeneReviews 459 Total variant submissions to ClinVar* 149354 Total variant submissions to ClinVar with clinical assertions* 102418 Total unique variant submissions to ClinVar with clinical assertions * 76606 Total genes, in submissions with assertions, with variants in one gene* 6801 Total genes, in submissions with assertions, with variants across multiple genes* 17763

Cross-CSER Annotation of 6 Variants Site MSH6 RYR1 FBN1 TSC2 TNNT2 LDLR c.2731C>T; c.1840C>T; c.4270C>G; c.736A>G; c.732G>T; c.967G>A; p.Arg911* p.Arg614Cys p.Pro1424Ala p.Thr246Ala p.Glu244Asp p.Gly323Ser Likely 1 Pathogenic VUS VUS VUS VUS pathogenic Likely 2 Pathogenic Pathogenic pathogenic/ VUS VUS VUS VUS 3 Pathogenic Pathogenic VUS VUS VUS VUS Likely 4 Pathogenic Pathogenic VUS VUS VUS pathogenic Likely Likely Likely 5 Pathogenic pathogenic/ VUS VUS pathogenic pathogenic VUS Pathogenic/ Likely Likely Likely 6 Pathogenic Likely VUS pathogenic/ pathogenic pathogenic pathogenic VUS Amendola et al, Genome Research, in press

Infrastructure Needs: Get annotations into ClinVar § UW has multiple molecular labs § UW Exome Lab pipelines to ClinVar § UW Lab Med molecular tests: 1000’s of cancer variants not submitted § UW Collage Diagnostic Lab: 1000 of variants not submitted § Outside lab reports to Clinical Service § Completed submitting BRCA1/2 § Hundreds more not submitted § Insufficient resources What if the EHR pushed annotated variants to ClinVar?

Regulatory Changes: Data Sharing, FDA

Regulatory Changes: FDA Oversight of Lab developed tests • Proposed FDA approval of tests • Freezes the test for each approval • Includes • Analysis pipeline • Which variants have clinical utility • Applies to research • Response to non-genetic test failures • Amer Assoc for Cancer Research: “must be FDA-approved” • Assoc for Molec Path: “Stifle innovation and freeze tests in time”