Exome sequencing identifies genetic variants in anophthalmia and microphthalmia

Jingjing Li; Wei Yang; Yuejun Jessie Wang; Chen Ma; Cynthia J Curry; Daniel McGoldrick; Deborah A Nickerson; Jessica X Chong; Elizabeth E Blue; James C Mullikin; Jennita Reefhuis; Wendy N Nembhard; Paul A Romitti; Martha M Werler; Marilyn L Browne; Andrew F Olshan; Richard H Finnell; Marcia L Feldkamp; Faith Pangilinan; Lynn M Almli; Mike J Bamshad; Lawrence C Brody; Mary M Jenkins; Gary M Shaw

doi:10.1002/ajmg.a.62874

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Exome sequencing identifies genetic variants in anophthalmia and microphthalmia

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Exome sequencing identifies genetic variants in anophthalmia and microphthalmia

Jingjing Li, Wei Yang, Yuejun Jessie Wang, Chen Ma, Cynthia J Curry, Daniel McGoldrick, Deborah A Nickerson, Jessica X Chong, Elizabeth E Blue, James C Mullikin, …

American journal of medical genetics. Part A, Vol.188(8), pp.2376-2388

06/18/2022

DOI: 10.1002/ajmg.a.62874

PMCID: PMC9283271

PMID: 35716026

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https://www.ncbi.nlm.nih.gov/pmc/articles/9283271View

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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.

Details

Title: Subtitle: Exome sequencing identifies genetic variants in anophthalmia and microphthalmia
Creators: Jingjing Li
Wei Yang
Yuejun Jessie Wang
Chen Ma
Cynthia J Curry
Daniel McGoldrick
Deborah A Nickerson
Jessica X Chong
Elizabeth E Blue
James C Mullikin
Jennita Reefhuis
Wendy N Nembhard
Paul A Romitti
Martha M Werler
Marilyn L Browne
Andrew F Olshan
Richard H Finnell
Marcia L Feldkamp
Faith Pangilinan
Lynn M Almli
Mike J Bamshad
Lawrence C Brody
Mary M Jenkins
Gary M Shaw
Resource Type: Journal article
Publication Details: American journal of medical genetics. Part A, Vol.188(8), pp.2376-2388
DOI: 10.1002/ajmg.a.62874
PMID: 35716026
PMCID: PMC9283271
NLM abbreviation: Am J Med Genet A
eISSN: 1552-4833
Grant note: DOI: 10.13039/100000030, name: Centers for Disease Control and Prevention, award: FOA DD09‐001, PA 02081, PA 96043; DOI: 10.13039/100005002, name: California Department of Public Health; DOI: 10.13039/100000002, name: National Institutes of Health; DOI: 10.13039/100000050, name: National Heart, Lung, and Blood Institute, award: U24 HG008956; DOI: 10.13039/100000051, name: National Human Genome Research Institute, award: UM1 HG006493; DOI: 10.13039/100007812, name: University of Washington
Language: English
Electronic publication date: 06/18/2022
Academic Unit: Epidemiology; Biostatistics
Record Identifier: 9984267559902771

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