Exome Sequencing Identifies Genetic Variants in Anophthalmia and Microphthalmia

Citation

Li, Jingjing; Yang, Wei; Wang, Yuejun J.; Ma, Chen; Curry, Cynthia J.; McGoldrick, Daniel; Nickerson, Deborah A.; Chong, Jessica X.; Blue, Elizabeth E.; & Mullikin, James C., et al. (2022). Exome Sequencing Identifies Genetic Variants in Anophthalmia and Microphthalmia. American Journal of Medical Genetics, 188(8), 2376-2388. PMCID: PMC9283271

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.

URL

http://dx.doi.org/10.1002/ajmg.a.62874

Reference Type

Journal Article

Year Published

2022

Journal Title

American Journal of Medical Genetics

Author(s)

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

Article Type

Regular

PMCID

PMC9283271

Data Set/Study

National Birth Defects Prevention Study (NBDPS)

Continent/Country

United States

State

Nonspecific

Race/Ethnicity

Hispanic
White
Black

ORCiD

Olshan - 0000-0001-9115-5128