Revealing hidden genetic diagnoses in the ocular anterior segment disorders.
exome and genome sequencing
eye
genomic medicine
ocular anterior segment dysgenesis
ophthalmology
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:
10 2020
10 2020
Historique:
received:
30
01
2020
accepted:
20
05
2020
revised:
19
05
2020
pubmed:
6
6
2020
medline:
28
4
2021
entrez:
6
6
2020
Statut:
ppublish
Résumé
Ocular anterior segment disorders (ASDs) are clinically and genetically heterogeneous, and genetic diagnosis often remains elusive. In this study, we demonstrate the value of a combined analysis protocol using phenotypic, genomic, and pedigree structure data to achieve a genetic conclusion. We utilized a combination of chromosome microarray, exome sequencing, and genome sequencing with structural variant and trio analysis to investigate a cohort of 41 predominantly sporadic cases. We identified likely causative variants in 54% (22/41) of cases, including 51% (19/37) of sporadic cases and 75% (3/4) of cases initially referred as familial ASD. Two-thirds of sporadic cases were found to have heterozygous variants, which in most cases were de novo. Approximately one-third (7/22) of genetic diagnoses were found in rarely reported or recently identified ASD genes including PXDN, GJA8, COL4A1, ITPR1, CPAMD8, as well as the new phenotypic association of Axenfeld-Rieger anomaly with a homozygous ADAMTS17 variant. The remainder of the variants were in key ASD genes including FOXC1, PITX2, CYP1B1, FOXE3, and PAX6. We demonstrate the benefit of detailed phenotypic, genomic, variant, and segregation analysis to uncover some of the previously "hidden" heritable answers in several rarely reported and newly identified ocular ASD-related disease genes.
Identifiants
pubmed: 32499604
doi: 10.1038/s41436-020-0854-x
pii: S1098-3600(21)00746-2
pmc: PMC7521990
doi:
Substances chimiques
FOXE3 protein, human
0
Forkhead Transcription Factors
0
Cytochrome P-450 CYP1B1
EC 1.14.14.1
ADAMTS Proteins
EC 3.4.24.-
ADAMTS17 protein, human
EC 3.4.24.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1623-1632Références
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