Medical Exome: Towards achieving complete coverage of disease related genes. A. Santani2,3, K. McDonald1, D. Mandelkar2, A. Ankala4, C. da Silva4, Z. Yu1, K. Cao1, H. Sharma2, R. Shakbatyan2, M. Lebo2, B. Funke1, M. Hegde4 1) Path & Lab Med, Philadelphia, PA; 2) Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Cambridge, MA; 3) Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Bosto; 4) Emory Genetics Laboratory, Emory University School of Medicine, Atlanta, GA 30047.

   Next Generation Sequencing (NGS) is being rapidly adopted by clinical laboratories and has allowed the development of disease targeted gene panels and more recently exome and genome sequencing. One drawback of gene panels is their suboptimal clinical sensitivity, which is often only marginally increased by adding novel genes. In contrast, exome and genome sequencing (ES/GS) interrogates all genes, but is flawed by incomplete coverage and interrogates a significant number of genes with no clinical relevance. The Medical Exome Project was launched to bridge the gap between gene panels and ES/GS by curating the genes of clinical relevance and improving the technical performance of exome capture assays by enhancing their coverage. In addition, exons with conserved paralogous sequences were excluded to avoid technical and analytical challenges. Over 4,499 genes with known or suspected roles in disease were extracted from literature and public databases. This list has been made available to the community through public resources such as the ICCG consortium and resources maintained at NCBI. A pilot curation was performed to evaluate the evidence for their role in disease by applying a scoring grid from 0 (no evidence) to 3 (definitely associated with disease). Of over 500 genes evaluated, approximately 20% did not have any evidence. An enhanced exome capture assay was developed using Agilents version 5 as a backbone and enhancing coverage of the 4,499 medically relevant genes. Intra- and inter laboratory clinical validation analyses of this enhanced exome (V5-PLUS) at a mean coverage of 100X indicated complete coverage of all exons was obtained for 3034 genes, whereas >95% coverage was obtained for the remaining 1465 genes. Most gene panels were covered to >99% and the rest of the exome was covered at >97%, which is an increase 5% over the Agilent V5. The performance was stable across 3 laboratories using 3 different data analysis pipelines. Alternate approaches are being employed to enhance the coverage of suboptimal genes. A collaborative, multi-center working group has been established to provide a detailed curation of the available literature to further evaluate the role of genes in disease. The availability of a curated medical exome will improve sensitivity and specificity of NGS based exome and genome sequencing and will provide a stepping stone for standardizing interpretation of genetic test results by clinical testing laboratories.

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