Low-level parental somatic mosaic SNVs in exomes from a large cohort of trios with diverse suspected Mendelian conditions.
Mendelian genomics
exome sequencing
parental somatic mosaicism
rare variants
Journal
Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
02
03
2020
accepted:
25
06
2020
revised:
25
06
2020
pubmed:
14
7
2020
medline:
29
4
2021
entrez:
14
7
2020
Statut:
ppublish
Résumé
The goal of this study was to assess the scale of low-level parental mosaicism in exome sequencing (ES) databases. 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. 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. 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.
Identifiants
pubmed: 32655138
doi: 10.1038/s41436-020-0897-z
pii: S1098-3600(21)00784-X
pmc: PMC7606563
mid: NIHMS1615434
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1768-1776Subventions
Organisme : NHGRI NIH HHS
ID : K08 HG008986
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD087292
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG006542
Pays : United States
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