Detection of mosaic variants using genome sequencing in a large pediatric cohort.
genome sequencing
genomic medicine
mosaicism
pediatric genetics
whole genome sequencing
Journal
American journal of medical genetics. Part A
ISSN: 1552-4833
Titre abrégé: Am J Med Genet A
Pays: United States
ID NLM: 101235741
Informations de publication
Date de publication:
03 2023
03 2023
Historique:
revised:
07
11
2022
received:
03
05
2022
accepted:
18
11
2022
pmc-release:
01
03
2024
pubmed:
24
12
2022
medline:
15
2
2023
entrez:
23
12
2022
Statut:
ppublish
Résumé
The increased use of next-generation sequencing has expanded our understanding of the involvement and prevalence of mosaicism in genetic disorders. We describe a total of eleven cases: nine in which mosaic variants detected by genome sequencing (GS) and/or targeted gene panels (TGPs) were considered to be causative for the proband's phenotype, and two of apparent parental mosaicism. Variants were identified in the following genes: PHACTR1, SCN8A, KCNT1, CDKL5, NEXMIF, CUX1, TSC2, GABRB2, and SMARCB1. In addition, we identified one large duplication including three genes, UBE3A, GABRB3, and MAGEL2, and one large deletion including deletion of ARFGAP1, EEF1A2, CHRNA4, and KCNQ2. All patients were enrolled in the NYCKidSeq study, a research program studying the communication of genomic information in clinical care, as well as the clinical utility and diagnostic yield of GS for children with suspected genetic disorders in diverse populations in New York City. We observed variability in the correlation between reported variant allele fraction and the severity of the patient's phenotype, although we were not able to determine the mosaicism percentage in clinically relevant tissue(s). Although our study was not sufficiently powered to assess differences in mosaicism detection between the two testing modalities, we saw a trend toward better detection by GS as compared with TGP testing. This case series supports the importance of mosaicism in childhood-onset genetic conditions and informs guidelines for laboratory and clinical interpretation of mosaic variants detected by GS.
Identifiants
pubmed: 36563179
doi: 10.1002/ajmg.a.63062
pmc: PMC10266700
mid: NIHMS1852855
doi:
Substances chimiques
MAGEL2 protein, human
0
Proteins
0
EEF1A2 protein, human
0
Peptide Elongation Factor 1
0
ARFGAP1 protein, human
0
GTPase-Activating Proteins
0
KCNT1 protein, human
0
Potassium Channels, Sodium-Activated
0
Nerve Tissue Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
699-710Subventions
Organisme : NHGRI NIH HHS
ID : U01 HG009610
Pays : United States
Informations de copyright
© 2022 Wiley Periodicals LLC.
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