Exploring the diagnostic yield of whole exome sequencing in a broad range of genetic conditions: the first 200 cases in the NCGENES study. N. T. Strande1, C. Bizon1,2, J. K. Booker1, K. R. Crooks1, A. K. M. Foreman1, G. T. Haskell1, M. A. Hayden1, K. Lee1, M. Lu1, L. Milko1, J. M. O'Daniel1, P. Owen1,2, B. C. Powell1, C. Skrzynia1, C. R. Tilley1, A. Treece1, D. Young1,2, K. C. Wilhelmsen1,2, K. E. Weck1, J. S. Berg1, J. P. Evans1 1) University of North Carolina at Chapel Hill, Chapel Hill, NC; 2) Renaissance Computing Institute.

   Massively parallel sequencing is an attractive modality for the diagnosis of monogenic disorders, but a major challenge with implementation in the clinical setting is determining which patients may be most amenable to diagnosis by this method. The NCGENES (North Carolina Clinical Genomic Evaluation by Next-generation Exome Sequencing) project is evaluating the use of whole exome sequencing as a diagnostic tool in patients with a variety of suspected genetic conditions where a clinical diagnosis was not made by traditional methods. We established diagnostic gene lists focused on certain clinical presentations in order to streamline our variant search. Variants in these genes were identified and annotated using an in-house variant analysis infrastructure and were manually reviewed to determine the pathogenicity of each variant. Variants with possible diagnostic significance (pathogenic, likely pathogenic, or variants of uncertain significance (VUS) in genes for which the patients phenotype was consistent with the disorder) were confirmed by Sanger sequencing and returned to the patients. Defining pathogenicity of individual variants is important, but it is also necessary to consider the phenotype to assess the overall diagnostic yield of such testing. We define positive results as a variant or variants that provide a definitive or probable explanation for the patients phenotype. We define several scenarios comprising the category of uncertain results: VUS in which there exists only uncertainty regarding whether the variant is deleterious, variants with possible contribution to disease but not entirely consistent with the phenotype, and heterozygous variants for recessive disorders consistent with the phenotype in which a second mutation was not identified. Overall, case-level results were positive (36/200) or uncertain (45/200) in 42.5% of patients. Diagnostic yield was strongly influenced by the diagnostic category. For example, among 49 patients with suspected hereditary cancer susceptibility, there were 4 (8.2%) positive, 10 (20.4%) uncertain, and 35 (71.4%) negative. In contrast, among 54 patients with primary neurological disorders, there were 13 (24.1%) positive, 14 (25.9%) uncertain, and 27 (50%) negative. Our results suggest that diagnostic yield of WES is not equal for all genetic conditions, and we discuss some reasons why this might be the case. This study aids in defining which patients ultimately may benefit most from WES.

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