Low-level parental somatic mosaic SNVs in exomes from a large cohort of trios with diverse suspected Mendelian conditions.

TitleLow-level parental somatic mosaic SNVs in exomes from a large cohort of trios with diverse suspected Mendelian conditions.
Publication TypeJournal Article
Year of Publication2020
AuthorsGambin, T, Liu, Q, Karolak, JA, Grochowski, CM, Xie, NG, Wu, LR, Yan, YHelen, Cao, Y, Akdemir, ZHCoban, Wilson, TA, Jhangiani, SN, Chen, E, Eng, CM, Muzny, D, Posey, JE, Yang, Y, Zhang, DY, Shaw, C, Liu, P, Lupski, JR, Stankiewicz, P
JournalGenet Med
Volume22
Issue11
Pagination1768-1776
Date Published2020 11
ISSN1530-0366
KeywordsExome, High-Throughput Nucleotide Sequencing, Humans, Mosaicism, Parents, Whole Exome Sequencing
Abstract

PURPOSE: The goal of this study was to assess the scale of low-level parental mosaicism in exome sequencing (ES) databases.

METHODS: We analyzed approximately 2000 family trio ES data sets from the Baylor-Hopkins Center for Mendelian Genomics (BHCMG) and Baylor Genetics (BG). Among apparent de novo single-nucleotide variants identified in the affected probands, we selected rare unique variants with variant allele fraction (VAF) between 30% and 70% in the probands and lower than 10% in one of the parents.

RESULTS: Of 102 candidate mosaic variants validated using amplicon-based next-generation sequencing, droplet digital polymerase chain reaction, or blocker displacement amplification, 27 (26.4%) were confirmed to be low- (VAF between 1% and 10%) or very low (VAF

CONCLUSION: Our computational pipeline enables robust discrimination between true and false positive candidate mosaic variants and efficient detection of low-level mosaicism in ES samples. We confirm that the presence of two or more alternate reads in the parental sample is a reliable predictor of low-level parental somatic mosaicism.
DOI10.1038/s41436-020-0897-z
Alternate JournalGenet Med
PubMed ID32655138
PubMed Central IDPMC7606563
Grant ListK08 HG008986 / HG / NHGRI NIH HHS / United States
R01 HD087292 / HD / NICHD NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States