De novo Mutations Identified in Clinical Whole Exome Sequencing. S. Pan1, F. Xia1, D. Muzny1, S. Plon1, 2, J. Lupski1, A. Beaudet1, R. Gibbs1, C. Eng1, Y. Yang1 1) Molecular and Human Genetics, Baylor College of Medicine, HOUSTON, TX, USA; 2) Pediatrics-Oncology, Baylor College of Medicine, HOUSTON, TX, USA.

   It has long been recognized that de novo pathogenic mutations contribute to genetic diseases especially early onset neurodevelopmental diseases. The occurrence of those de novo changes results in the relatively constant prevalence of related genetic disorders in human populations irrespective of severely reduced fitness. However, the exact prevalence and spectrum of de novo mutations in these diseases remain unknown. We have accumulated a large patient cohort of 2000 unrelated patients referred for clinical WES, of which 87% had early onset neurologic disorders. Through whole exome sequencing (WES) followed by family-based Sanger confirmation, molecular diagnoses were made in 504 patients, including 23 with two diagnoses. The WES diagnoses included 280 autosomal dominant (AD), 181 autosomal recessive (AR), 65 X-linked (XL) and 1 mitochondrial disorders. The total known de novo events (249) accounts for ~13% (249/2000) of all clinical WES cases in our cohort and 56% (249/504) of all WES cases with molecular diagnoses. About 74% (208/280) of the AD disorders (87% if excluding cases without parental studies), 62% (40/65) XL disorders as well as the one case with pathogenic change in the mitochondrial genome resulted from de novo mutations in the causal genes. The de novo changes included 127 missense, 42 nonsense, 11 splicing, 64 frameshift and 4 inframe changes. Of the 177 point mutations, 106 (59.9%) were C>T or G>A changes occurred at the CpG sites. Notably, mosaicism of mutant alleles was identified in 5 probands (3 with AD and 2 with XL disorders). The 249 total de novo changes were distributed in 122 genes, among which ARID1B (14X), ANKRD11 (7X) and KCNT1 (7X) were the most frequently affected. Recurrent point mutations in mutation hotspots were observed in ACTA2 (2X), ANKRD11 (2X), KCNT1 (2X) and PACS1 (3X) genes. In summary, we have identified a spectrum of de novo mutations in our large clinical WES cohort. Although individually rare, this group of de novo mutations contributed to the molecular diagnoses for a significant portion of clinical WES cases. Together with associated clinical phenotypes, this collection of de novo mutations can provide more insight in our understanding of the etiology of sporadic genetic diseases.

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