Disease-associated mosaic variation in clinical exome sequencing: a two-year pediatric tertiary care experience.

Autor:	Miller CR; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.; Department of Pathology., Lee K; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.; Department of Pathology., Pfau RB; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.; Department of Pathology.; Department of Pediatrics, The Ohio State University, Columbus, Ohio 43210, USA., Reshmi SC; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.; Department of Pathology.; Department of Pediatrics, The Ohio State University, Columbus, Ohio 43210, USA., Corsmeier DJ; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA., Hashimoto S; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA., Dave-Wala A; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA., Jayaraman V; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA., Koboldt D; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.; Department of Pediatrics, The Ohio State University, Columbus, Ohio 43210, USA., Matthews T; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA., Mouhlas D; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA., Stein M; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA., McKinney A; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA., Grossman T; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA., Kelly BJ; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA., White P; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.; Department of Pediatrics, The Ohio State University, Columbus, Ohio 43210, USA., Magrini V; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.; Department of Pediatrics, The Ohio State University, Columbus, Ohio 43210, USA., Wilson RK; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.; Department of Pediatrics, The Ohio State University, Columbus, Ohio 43210, USA., Mardis ER; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.; Department of Pediatrics, The Ohio State University, Columbus, Ohio 43210, USA., Cottrell CE; The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.; Department of Pathology.; Department of Pediatrics, The Ohio State University, Columbus, Ohio 43210, USA.
Jazyk:	angličtina
Zdroj:	Cold Spring Harbor molecular case studies [Cold Spring Harb Mol Case Stud] 2020 Jun 12; Vol. 6 (3). Date of Electronic Publication: 2020 Jun 12 (Print Publication: 2020).
DOI:	10.1101/mcs.a005231
Abstrakt:	Exome sequencing (ES) has become an important tool in pediatric genomic medicine, improving identification of disease-associated variation due to assay breadth. Depth is also afforded by ES, enabling detection of lower-frequency mosaic variation compared to Sanger sequencing in the studied tissue, thus enhancing diagnostic yield. Within a pediatric tertiary-care hospital, we report two years of clinical ES data from probands evaluated for genetic disease to assess diagnostic yield, characteristics of causal variants, and prevalence of mosaicism among disease-causing variants. Exome-derived, phenotype-driven variant data from 357 probands was analyzed concurrent with parental ES data, when available. Blood was the source of nucleic acid. Sequence read alignments were manually reviewed for all assessed variants. Sanger sequencing was used for suspected de novo or mosaic variation. Clinical provider notes were reviewed to determine concordance between laboratory-reported data and the ordering provider's interpretation of variant-associated disease causality. Laboratory-derived diagnostic yield and provider-substantiated diagnoses had 91.4% concordance. The cohort returned 117 provider-substantiated diagnoses among 115 probands for a diagnostic yield of 32.2%. De novo variants represented 64.9% of disease-associated variation within trio analyses. Among the 115 probands, five harbored disease-associated somatic mosaic variation. Two additional probands were observed to inherit a disease-associated variant from an unaffected mosaic parent. Among inheritance patterns, de novo variation was the most frequent disease etiology. Somatic mosaicism is increasingly recognized as a significant contributor to genetic disease, particularly with increased sequence depth attainable from ES. This report highlights the potential and importance of detecting mosaicism in ES. (© 2020 Miller et al.; Published by Cold Spring Harbor Laboratory Press.)
Databáze:	MEDLINE
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