Exome Sequencing Identifies Novel Genes Underlying Primary Congenital Glaucoma in the National Birth Defects Prevention Study

Authors

Elizabeth E Blue
Kristin J Moore
Kari E North
Tania A Desrosiers
Suzan L Carmichael
Janson J White
Jessica X Chong
Michael J Bamshad
Mary M Jenkins
Lynn M Almli
Lawrence C Brody
Sharon F Freedman
Jennita Reefhuis
Paul A Romitti
Gary M Shaw
Martha Werler
Denise M Kay
Marilyn L Browne
Marcia L Feldkamp
Richard H Finnell
Wendy N Nembhard
Faith Pangilinan
Andrew F Olshan
National Institutes of Health Intramural Sequencing Center
University of Washington Center for Mendelian Genomics
National Birth Defects Prevention Study

Language

English

Publication Date

7-1-2024

Journal

Birth Defects Research

DOI

10.1002/bdr2.2384

PMID

38990107

PMCID

PMC11245170

PubMedCentral® Posted Date

7-1-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Background: Primary congenital glaucoma (PCG) affects approximately 1 in 10,000 live born infants in the United States (U.S.). PCG has a autosomal recessive inheritance pattern, and variable expressivity and reduced penetrance have been reported. Likely causal variants in the most commonly mutated gene, CYP1B1, are less prevalent in the U.S., suggesting that alternative genes may contribute to the condition. This study utilized exome sequencing to investigate the genetic architecture of PCG in the U.S. and to identify novel genes and variants.

Methods: We studied 37 family trios where infants had PCG and were part of the National Birth Defects Prevention Study (births 1997-2011), a U.S. multicenter study of birth defects. Samples underwent exome sequencing and sequence reads were aligned to the human reference sample (NCBI build 37/hg19). Variant filtration was conducted under de novo and Mendelian inheritance models using GEMINI.

Results: Among candidate variants, CYP1B1 was most represented (five trios, 13.5%). Twelve probands (32%) had potentially pathogenic variants in other genes not previously linked to PCG but important in eye development and/or to underlie Mendelian conditions with potential phenotypic overlap (e.g., CRYBB2, RXRA, GLI2).

Conclusion: Variation in the genes identified in this population-based study may help to further explain the genetics of PCG.

Keywords

Humans, Glaucoma, Cytochrome P-450 CYP1B1, Female, Male, Exome Sequencing, United States, Exome, Mutation, Genetic Predisposition to Disease, Infant, Infant, Newborn, CYP1B1, birth defects, congenital glaucoma, newborn eye abnormalities, genetics, mutations

Published Open-Access

yes

Recommended Citation

Blue, Elizabeth E; Moore, Kristin J; North, Kari E; et al., "Exome Sequencing Identifies Novel Genes Underlying Primary Congenital Glaucoma in the National Birth Defects Prevention Study" (2024). Faculty and Staff Publications. 4865.
https://digitalcommons.library.tmc.edu/baylor_docs/4865