Clinical utility of the first one thousand clinical whole exome sequencing tests: molecular diagnostic rate, changes in medical management, and the impact of incidental findings. C. Eng1,3, D. Muzny2,3, J. Reid2, M. Bainbridge2, A. Willis1, M. Landsverk1, J. Beuten1, M. Leduc1, P. Ward1, A. Braxton1, M. Hardison1, Z. Niu1, R. Person1, F. Xia1, M. Bekheirnia1, J. Scull1, S. Wen1, J. Zhang1, A. Hawes2, C. Buhay2, Y. Ding3, M. Scheel3, N. Saada3, W. Liu3, J. Ma3, J. Chandarana3, L. Dolores-Freiberg3, W. Alcaraz1, H. Cui1, M. Walkiewicz1, E. Boerwinkle2, S. Plon1, J. Lupski1, A. Beaudet1, R. Gibbs2, Y. Yang1 1) Dept Molec & Human Genetics, Baylor Col Medicine, Houston, TX; 2) Human Genome Sequencing Center, Baylor Col Medicine, Houston, TX; 3) Whole Genome Laboratory, Baylor Col Medicine, Houston, TX.

   We developed and optimized technical, bioinformatic and interpretive whole exome sequencing (WES) pipelines in a CAP and CLIA certified lab to identify causative mutations underlying disease phenotypes in undiagnosed patients being evaluated clinically for genetic disorders. Approximately 13 Gb of data were generated for each clinical sample and a mean coverage of 160X was achieved with >95% of the targeted bases covered at 20X or higher. Of the 18773 genes in our exome capture 90% have >90% of the coding regions covered by WES. Since October 2011, over 1700 WES tests have been submitted to our clinical lab on a fee-for-service basis. The majority of ordering physicians are medical geneticists and neurologists evaluating pediatric-aged patients with neurologic phenotypes who previously had a variety of genetic and other(e.g. imaging) tests without an etiologic diagnosis. To date, 1000 WES tests have been completed and results reported. We identified 367 causative mutant alleles in 265 patients, achieving an overall molecular diagnostic rate of 26%. The solved diagnoses include 149 patients with autosomal dominant, 81 with autosomal recessive and 27 with X-linked disorders. For AD conditions, 91 patients carry de novo mutations, and the remaining 58 patients have mutations either inherited from a parent or of unknown inheritance status. Eight patients were found to have two genetic diagnoses which may have confounded recognition of the underlying syndromes due to blended phenotypes. Recurrent diagnoses include six cases of Noonan spectrum disorder and four cases of Cornelia deLange, as well as 19 intellectual disability cases caused by mutations in SWI/SNF complex genes including 12 mutations in the ARID1B gene. Interestingly, 20% of the diagnoses have been made in genes identified and reported in the literature during the last 3 years. Examples of situations in which the WES led to changes in treatment include three patients diagnosed with congenital myasthenia. Medically actionable incidental results unrelated to the indication for testing were reported for 77 patients (7.7%);the majority of conditions reported in this category were mutations in cardiovascular or cancer predisposition genes. This study evaluates our first 1000 completed clinical WES cases and demonstrates the clinical utility of WES as an efficient diagnostic approach for patients with non-specific or unusual clinical presentations suggestive of underlying genetic disorders.

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