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

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 <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.