Exome sequencing identifies novel genes underlying primary congenital glaucoma in the National Birth Defects Prevention Study

Authors:
Publisher website
Google Scholar
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.
Funding Information
  • National Human Genome Research Institute (U01 HG011744, UM1 HG006493, U24 HG011746, U24 HG008956)
  • Centers for Disease Control and Prevention (U01DD001231, PA #96043, PA #02081, FOA #DD09‐001, FOA #DD13‐003, NOFO #DD18‐001)

This publication has 78 references indexed in Scilit: