Ozge Ceyhan-Birsoy1,2,3, Kalotina Machini1,2,3, Matthew S Lebo1,2,3, Tim W Yu3,4,5, Pankaj B Agrawal3,4,6, Richard B Parad3,7, Ingrid A Holm3,4, Amy McGuire8, Robert C Green3,9,10, Alan H Beggs3,4, Heidi L Rehm1,2,3,10. 1. Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Cambridge, Massachusetts, USA. 2. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA. 3. Harvard Medical School, Boston, Massachusetts, USA. 4. Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts, USA. 5. Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA. 6. Division of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts, USA. 7. Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. 8. Center for Medical Ethics and Health Policy, Baylor College of Medicine, Houston, Texas, USA. 9. Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. 10. The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Abstract
PURPOSE: Genomic sequencing (GS) for newborns may enable detection of conditions for which early knowledge can improve health outcomes. One of the major challenges hindering its broader application is the time it takes to assess the clinical relevance of detected variants and the genes they impact so that disease risk is reported appropriately. METHODS: To facilitate rapid interpretation of GS results in newborns, we curated a catalog of genes with putative pediatric relevance for their validity based on the ClinGen clinical validity classification framework criteria, age of onset, penetrance, and mode of inheritance through systematic evaluation of published evidence. Based on these attributes, we classified genes to guide the return of results in the BabySeq Project, a randomized, controlled trial exploring the use of newborn GS (nGS), and used our curated list for the first 15 newborns sequenced in this project. RESULTS: Here, we present our curated list for 1,514 gene-disease associations. Overall, 954 genes met our criteria for return in nGS. This reference list eliminated manual assessment for 41% of rare variants identified in 15 newborns. CONCLUSION: Our list provides a resource that can assist in guiding the interpretive scope of clinical GS for newborns and potentially other populations.Genet Med advance online publication 12 January 2017.
PURPOSE: Genomic sequencing (GS) for newborns may enable detection of conditions for which early knowledge can improve health outcomes. One of the major challenges hindering its broader application is the time it takes to assess the clinical relevance of detected variants and the genes they impact so that disease risk is reported appropriately. METHODS: To facilitate rapid interpretation of GS results in newborns, we curated a catalog of genes with putative pediatric relevance for their validity based on the ClinGen clinical validity classification framework criteria, age of onset, penetrance, and mode of inheritance through systematic evaluation of published evidence. Based on these attributes, we classified genes to guide the return of results in the BabySeq Project, a randomized, controlled trial exploring the use of newborn GS (nGS), and used our curated list for the first 15 newborns sequenced in this project. RESULTS: Here, we present our curated list for 1,514 gene-disease associations. Overall, 954 genes met our criteria for return in nGS. This reference list eliminated manual assessment for 41% of rare variants identified in 15 newborns. CONCLUSION: Our list provides a resource that can assist in guiding the interpretive scope of clinical GS for newborns and potentially other populations.Genet Med advance online publication 12 January 2017.
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