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

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 datasets from the Baylor-Hopkins Center for Mendelian Genomics (BHCMG) and Baylor Genetics (BG). Among apparent de novo single nucleotide variants (SNVs) identified in the affected probands, we selected rare unique variants with variant allele fraction (VAF) between 30-70% in the probands and lower than 10% in one of the parents. RESULTS: Out of 102 candidate mosaic variants validated using amplicon-based NGS, droplet digital PCR, or blocker displacement amplification, 27 (26.4%) were confirmed to be low- (VAF between 1-10%) 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.