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

Genet Med. 2020 Nov;22(11):1768-1776. doi: 10.1038/s41436-020-0897-z. Epub 2020 Jul 13.


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.

Keywords: Mendelian genomics; exome sequencing; parental somatic mosaicism; rare variants.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Exome Sequencing
  • Exome* / genetics
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Mosaicism*
  • Parents