. 2024 Jul;116(7):e2384.

doi: 10.1002/bdr2.2384.

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

Elizabeth E Blue^{1

2}, Kristin J Moore³, Kari E North³, Tania A Desrosiers³, Suzan L Carmichael⁴, Janson J White⁵, Jessica X Chong^{2

5}, Michael J Bamshad^{2

5

6

7}, Mary M Jenkins⁸, Lynn M Almli⁸, Lawrence C Brody⁹, Sharon F Freedman¹⁰, Jennita Reefhuis⁸, Paul A Romitti¹¹, Gary M Shaw⁴, Martha Werler^{12

13}, Denise M Kay¹⁴, Marilyn L Browne^{15

16}, Marcia L Feldkamp¹⁷, Richard H Finnell¹⁸, Wendy N Nembhard¹⁹, Faith Pangilinan⁹, Andrew F Olshan³; National Institutes of Health Intramural Sequencing Center; University of Washington Center for Mendelian Genomics; National Birth Defects Prevention Study

Affiliations

¹ Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington, USA.
² Brotman-Baty Institute for Precision Medicine, Seattle, Washington, USA.
³ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
⁴ Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.
⁵ Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA.
⁶ Division of Genetic Medicine, Seattle Children's Hospital, Seattle, Washington, USA.
⁷ Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA.
⁸ National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
⁹ Division of Genomics and Society, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
¹⁰ Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, USA.
¹¹ Department of Epidemiology, College of Public Health, The University of Iowa, Iowa City, Iowa, USA.
¹² Department of Epidemiology, School of Public Health, Boston University, Boston, Massachusetts, USA.
¹³ Slone Epidemiology Center at Boston University, Boston, Massachusetts, USA.
¹⁴ Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, New York, USA.
¹⁵ New York State Department of Health, Birth Defects Registry, Albany, New York, USA.
¹⁶ Department of Epidemiology and Biostatistics, University at Albany School of Public Health, Rensselaer, New York, USA.
¹⁷ Division of Medical Genetics, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah, USA.
¹⁸ Center for Precision Environmental Health, Departments of Molecular and Cellular Biology and Medicine, Baylor College of Medicine, Houston, Texas, USA.
¹⁹ Department of Epidemiology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.

PMID: 38990107
PMCID: PMC11245170
DOI: 10.1002/bdr2.2384

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

Elizabeth E Blue et al. Birth Defects Res. 2024 Jul.

. 2024 Jul;116(7):e2384.

doi: 10.1002/bdr2.2384.

Authors

Affiliations

¹ Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington, USA.
² Brotman-Baty Institute for Precision Medicine, Seattle, Washington, USA.
³ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
⁴ Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.
⁵ Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA.
⁶ Division of Genetic Medicine, Seattle Children's Hospital, Seattle, Washington, USA.
⁷ Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA.
⁸ National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
⁹ Division of Genomics and Society, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
¹⁰ Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, USA.
¹¹ Department of Epidemiology, College of Public Health, The University of Iowa, Iowa City, Iowa, USA.
¹² Department of Epidemiology, School of Public Health, Boston University, Boston, Massachusetts, USA.
¹³ Slone Epidemiology Center at Boston University, Boston, Massachusetts, USA.
¹⁴ Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, New York, USA.
¹⁵ New York State Department of Health, Birth Defects Registry, Albany, New York, USA.
¹⁶ Department of Epidemiology and Biostatistics, University at Albany School of Public Health, Rensselaer, New York, USA.
¹⁷ Division of Medical Genetics, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah, USA.
¹⁸ Center for Precision Environmental Health, Departments of Molecular and Cellular Biology and Medicine, Baylor College of Medicine, Houston, Texas, USA.
¹⁹ Department of Epidemiology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.

PMID: 38990107
PMCID: PMC11245170
DOI: 10.1002/bdr2.2384

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: CYP1B1; birth defects; congenital glaucoma; genetics; mutations; newborn eye abnormalities.

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Cited by

GREGoR: Accelerating Genomics for Rare Diseases.
Dawood M, Heavner B, Wheeler MM, Ungar RA, LoTempio J, Wiel L, Berger S, Bernstein JA, Chong JX, Délot EC, Eichler EE, Gibbs RA, Lupski JR, Shojaie A, Talkowski ME, Wagner AH, Wei CL, Wellington C, Wheeler MT; GREGoR Partner Members; Carvalho CMB, Gifford CA, May S, Miller DE, Rehm HL, Sedlazeck FJ, Vilain E, O'Donnell-Luria A, Posey JE, Chadwick LH, Bamshad MJ, Montgomery SB; Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium. Dawood M, et al. ArXiv [Preprint]. 2024 Dec 18:arXiv:2412.14338v1. ArXiv. 2024. PMID: 39764392 Free PMC article. Preprint.

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

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

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