Whole Genome Sequencing in a Healthy Population: Processes, Challenges, and Insights. CS. Richards1, P. Jain1, MO. Dorschner2,3, DA. Nickerson3, GP. Jarvik3,4, LM. Amendola4, DK. Simpson7, A. Rope7, J. Reiss7,8, K. Kennedy8, DI. Quigley9, J. Berg10, C. Harding1, M. Gilmore7, P. Himes7, B. Wilfond5,6, KAB. Goddard11 on behalf of the NextGen Project Team 1) Department of Molecular and Medical Genetics, Knight Diagnostic Laboratories, Oregon Health & Science University, Portland, OR; 2) Pathology, Division of Bioethics, University of Washington, Seattle, WA; 3) Genome Sciences, Division of Bioethics, University of Washington, Seattle, WA; 4) Department of Medicine, Division of Medical Genetics, Division of Bioethics, University of Washington, Seattle, WA; 5) Department of Pediatrics, Division of Bioethics, University of Washington, Seattle, WA; 6) Truman Katz Center for Pediatric Bioethics, Seattle Childrens Hospital, Seattle, WA; 7) Department of Medical Genetics, Kaiser Permanente Northwest, Portland, OR; 8) Obstetrics and Gynecology, Kaiser Permanente Northwest, Portland, OR; 9) Laboratory, Kaiser Permanente Northwest, Portland, OR; 10) Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, NC; 11) Center for Health Research, Kaiser Permanente Northwest, Portland, OR.
We are performing carrier screening of a healthy population (reproductive age preconception) in a large integrated healthcare delivery system using whole genome sequencing (WGS). Our strategy is to test the female partner first, and if positive, offer testing to the partner. Our carrier screen includes about 500 genes. Our analytic pipeline includes: (1) WGS testing in the Illumina CLIA laboratory; (2) data processing including alignment and variant annotation using the SeattleSeq pipeline (Nickerson laboratory); (3) data analysis, including filtering variants and classification for the carrier test, Sanger confirmation of findings, and reporting in the Knight Diagnostic Laboratory (KDL); and (4) data analysis for incidental findings (Nickerson laboratory using the expanded incidental findings list of 114 genes described by Dorschner, 2013), and transfer of results to KDL for Sanger confirmation of findings and reporting of results. Presently, 11 patients are enrolled with 4 cases reported. To date 4 of the 5 variants reported have been novel, including two duplications leading to frameshifts (SACS gene associated with spastic ataxia, Charlevoix-Saguenay type; SLC3A1 gene associated with cystinuria), one splicing variant (CRTAP gene associated with osteogenesis imperfect type VII), and one nonsense variant (NAGA gene associated with Schindler disease types I and II). One known pathogenic missense variant was identified (AGXT gene associated with hyperoxaluria type 1). Most of these disorders are rare, and thus not present on most carrier screening panels. To date two patients carry two variants each, one patient carries only one variant, and one patient had no detectable reportable variants. Only pathogenic or likely pathogenic variants are reported, as our criteria for calling and classifying variants is very stringent. We will present metrics for the testing which include data filtering strategies for identifying disease-causing variants and time for analysis and classification of each variant. We have found that each patients data presents a new learning experience. A Return of Results Committee composed of clinical and laboratory geneticists and genetic counselors, is consulted for expertise and guidance. We anticipate that at least 25 patient results, including incidental findings, will be returned prior to this presentation.
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