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

Tomasz Gambin , Qian Liu , Justyna Karolak , Christopher M. Grochowski , Nina G. Xie , Tzong-Lin Wu , Yan Helen Yan , Ye Cao , Zeynep H. Coban Akdemir , Theresa A. Wilson , Shalini N. Jhangiani , Ed Chen , Christine M. Eng , Donna Muzny , Jennifer E. Posey , Y. Yang , Dan Zhang , Chad Shaw , Pengfei Liu , James R. Lupski , P. Stankiewicz


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 <1%) level mosaic. Detection precision in parental samples with two or more alternate reads was 63.6% (BHCMG) and 43.6% (BG). In nine investigated individuals, we observed variability of mosaic ratios among blood, saliva, fibroblast, buccal, hair, and urine samples. 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.
Author Tomasz Gambin (FEIT / IN)
Tomasz Gambin,,
- The Institute of Computer Science
, Qian Liu
Qian Liu,,
, Justyna Karolak
Justyna Karolak,,
, Christopher M. Grochowski
Christopher M. Grochowski,,
, Nina G. Xie
Nina G. Xie,,
, Tzong-Lin Wu
Tzong-Lin Wu,,
, Yan Helen Yan
Yan Helen Yan,,
, Ye Cao
Ye Cao,,
, Zeynep H. Coban Akdemir
Zeynep H. Coban Akdemir,,
, Theresa A. Wilson
Theresa A. Wilson,,
et al.`
Journal seriesGenetics in Medicine, ISSN 1098-3600, e-ISSN 1530-0366
Issue year2020
Publication size in sheets0.5
ASJC Classification2716 Genetics(clinical)
Languageen angielski
Score (nominal)200
Score sourcejournalList
ScoreMinisterial score = 200.0, 18-09-2020, ArticleFromJournal
Publication indicators WoS Citations = 0; Scopus SNIP (Source Normalised Impact per Paper): 2018 = 3.488; WoS Impact Factor: 2018 = 8.683 (2) - 2018=9.827 (5)
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