Exome sequencing identifies genetic variants in anophthalmia and microphthalmia
Year: 2022
Type: article
Study design: Observational Study
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.
DOI: 10.1002/ajmg.a.62874
Authors: 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, NISC Comparative Sequencing Program, the National Birth Defects Prevention Study
Institutions: University of California, San Francisco, Parker Institute for Cancer Immunotherapy, Stanford Medicine, Stanford University, University of Washington, Brotman Baty Institute, National Institutes of Health, National Human Genome Research Institute, Centers for Disease Control and Prevention, National Center on Birth Defects and Developmental Disabilities, University of Arkansas for Medical Sciences, University of Iowa, Boston University, New York State Department of Health, University at Albany, State University of New York, University of North Carolina at Chapel Hill, Baylor College of Medicine, University of Utah
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Awards: G1068064772, G1145863725, COMPONENT A: ARKANSAS PROPOSAL TO PARTICIPATE IN THE BIRTH DEFECTS STUDY TO EVALUATE PREGNANCY EXPOSURES (BD-STEPS II), BIRTH DEFECTS STUDY TO EVALUATE PREGNANCY EXPOSURES, NEW YORK STATE COMPONENT A: BD-STEPS II CORE, RFA-DD-18-001 BIRTH DEFECTS STUDY TO EVALUATE PREGNANCY EXPOSURES (BD-STEPS) II CORE & COMPONENT B STEPS -STILLBIRTH, G2660465552, G2663813066, CALIFORNIA CENTER OF BD-STEPS II FINDING CAUSES AND PREVENTIVES OF BIRTH DEFECTS, G334973597, G3514394873, G4091723164, G4368308242, G6000609453, G6430162933, G685353292, G73439054, UW Center for Mendelian Genomics, BIRTH DEFECTS STUDY TO EVALUATE PREGNANCY EXPOSURES (BD-STEPS) CORE? ARKANSAS CENTER AND STILLBIRTH - BIRTH DEFECTS STUDY TO EVALUATE PREGNANCY EXPOSURES (BD-STEPS) CORE- ARKANSAS CENTER AND STILLBIRTH, G9000275289, G9000345790
OpenAlex ID: W4283079097