Grandparental genotyping enhances exome variant interpretation.
Adult
Child
Epilepsy
/ genetics
Exome
/ genetics
Female
Genetic Predisposition to Disease
Genetic Testing
Genotype
Grandparents
Humans
Hypoplastic Left Heart Syndrome
/ genetics
Infant, Newborn
Male
Mosaicism
Mutation
Parents
Receptor, Notch1
/ genetics
Repressor Proteins
/ genetics
SOXE Transcription Factors
/ genetics
Exome Sequencing
incomplete penetrance
mosaicism
skewed X-inactivation
trio exome sequencing
variable expressivity
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:
04 2020
04 2020
Historique:
received:
16
10
2019
revised:
09
12
2019
accepted:
03
01
2020
pubmed:
7
2
2020
medline:
4
2
2021
entrez:
7
2
2020
Statut:
ppublish
Résumé
Trio exome sequencing is a powerful tool in the molecular investigation of monogenic disorders and provides an incremental diagnostic yield over proband-only sequencing, mainly due to the rapid identification of de novo disease-causing variants. However, heterozygous variants inherited from unaffected parents may be inadvertently dismissed, although multiple explanations are available for such scenarios including mosaicism in the parent, incomplete penetrance, imprinting, or skewed X-inactivation. We report three probands, in which a pathogenic or likely pathogenic variant was identified upon exome sequencing, yet was inherited from an unaffected parent. Segregation of the variants (in NOTCH1, PHF6, and SOX10) in the grandparent generation revealed that the variant was de novo in each case. Additionally, one proband had skewed X-inactivation. We discuss the possible genetic mechanism in each case, and urge caution in data interpretation of exome sequencing data. We illustrate the utility of expanding segregation studies to the grandparent generation and demonstrate the impact on exome interpretation strategies, by showing that objective genotype data can overcome subjective parental report of lack of symptoms.
Identifiants
pubmed: 32027463
doi: 10.1002/ajmg.a.61511
doi:
Substances chimiques
NOTCH1 protein, human
0
PHF6 protein, human
0
Receptor, Notch1
0
Repressor Proteins
0
SOX10 protein, human
0
SOXE Transcription Factors
0
Types de publication
Case Reports
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
689-696Informations de copyright
© 2020 Wiley Periodicals, Inc.
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