Clinical Whole Exome Sequencing Reveals Contribution of Rare Genetic Events to Undiagnosed Disease. C. M. Eng1, D. Muzny2, F. Xia1, Z. Niu1, R. Person1, Y. Ding2, P. Ward1, A. Braxton1, M. Wang2, C. Buhay2, N. Veeraraghavan2, A. Hawes2, T. Chiang2, M. Leduc1, J. Beuten1, J. Zhang1, W. He1, J. Scull1, A. Willis1, M. Landsverk1, W. Craigen1, M. Bekeirnia1, P. Liu1, S. Wen1, W. Alcaraz1, H. Cui1, M. Walkiewicz1, M. Bainbridge2, E. Boerwinkle2,3, A. L. Beaudet1, J.R. Lupski1,2, S.E. Plon1,2, R.A. Gibbs1,2, Y Yang1 1) Dept Molec & Human Genetics, Baylor Col Medicine, Houston, TX; 2) Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX; 3) University of Texas Health Sciences Branch, 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. We previously reported (Yang, et al NEJM 2013;369:1502) implementation of a pilot program to provide WES on a clinical basis and a summary of the first 250 cases. The current study examines the subsequent 2000 patients referred for clinical WES yielding insight into the underlying disease mechanisms in patients with Mendelian disorders. Approximately 10 Gb of data were generated for each clinical sample with a mean coverage of 100X and >95% of the targeted bases covered at >20X. The mitochondrial genome was sequenced concurrently. Approximately 87% were pediatric patients with neurologic phenotypes. Diagnoses were based on mutation severity according to ACMG guidelines for variant interpretation, appropriate inheritance patterns, phenotypic fit and feedback from referring physicians. An overall molecular diagnosis was reported for 504 patients (25%). Patients with specific neurologic findings e.g., seizures had the highest diagnostic rate (36.1%). Mendelian disease patterns included: 280 (53.1%) autosomal dominant (of which at least 74% were shown to have arisen de novo), 181 (34.3%) autosomal recessive, 65 (12.3%) X-linked and 1 (0.2%) mitochondrial. Twenty-three patients (4.6% of those with diagnoses) had blended phenotypes resulting from two underlying single gene defects. In five patients, uniparental isodisomy (UPD) unmasked autosomal recessive mutations resulting in markedly different recurrence risks for these families. Of the solved cases, 30% harbored causative mutations in disease genes reported since 2011. Medically actionable incidental findings were reported in 95 subjects (4.8%), including 60 patients (3%) with variants in genes recommended for reporting by the ACMG. Referred cases without a diagnosis have the option of entering a research protocol at our institution potentially leading to novel gene discovery, such as that recently reported for AHDC1. WES is an important diagnostic tool that provides a molecular diagnosis for 25% of previously undiagnosed patients. Further examination of the results of this large cohort reveals data on the mechanisms of genetic disorders such as blended phenotypes, de novo mutations, and rare genetic events such as UPD.

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