Publication Date
8-1-2022
Journal
American Journal of Medical Genetics Part A
DOI
10.1002/ajmg.a.62874
PMID
35716026
PMCID
PMC9283271
PubMedCentral® Posted Date
8-1-2023
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Keywords
Anophthalmos, Exome, Humans, Infant, Microphthalmos, Mutation, Missense, Exome Sequencing, Congenital abnormalities, newborn eye abnormalities, genetic epidemiology
Abstract
Anophthalmia and microphthalmia (A/M) are rare birth defects affecting up to 2 per 10,000 live births. These conditions are manifested by the absence of an eye or reduced eye volumes within the orbit leading to vision loss. Although clinical case series suggest a strong genetic component in A/M, few systematic investigations have been conducted on potential genetic contributions owing to low population prevalence. To overcome this challenge, we utilized DNA samples and data collected as part of the National Birth Defects Prevention Study (NBDPS). The NBDPS employed multi-center ascertainment of infants affected by A/M. We performed exome sequencing on 67 family trios and identified numerous genes affected by rare deleterious nonsense and missense variants in this cohort, including de novo variants. We identified 9 nonsense changes and 86 missense variants that are absent from the reference human population (Genome Aggregation Database), and we suggest that these are high priority candidate genes for A/M. We also performed literature curation, single cell transcriptome comparisons, and molecular pathway analysis on the candidate genes and performed protein structure modeling to determine the potential pathogenic variant consequences on PAX6 in this disease.
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Biological Phenomena, Cell Phenomena, and Immunity Commons, Congenital, Hereditary, and Neonatal Diseases and Abnormalities Commons, Life Sciences Commons, Medical Cell Biology Commons, Medical Genetics Commons, Medical Microbiology Commons, Medical Molecular Biology Commons, Medical Specialties Commons
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