Abstract
Primary congenital glaucoma is a trabecular meshwork dysgenesis with resultant increased intraocular pressure and ocular damage. CYP1B1 mutations remain the most common identifiable genetic cause. However, important questions about the penetrance of CYP1B1-related congenital glaucoma remain unanswered. Furthermore, mutations in other genes have been described although their exact contribution and potential genetic interaction, if any, with CYP1B1 mutations are not fully explored. In this study, we employed modern genomic approaches to re-examine CYP1B1-related congenital glaucoma. A cohort of 193 patients (136 families) diagnosed with congenital glaucoma. We identified biallelic CYP1B1 mutations in 80.8% (87.5 and 66.1% in familial and sporadic cases, respectively, p < 0.0086). The large family size of the study population allowed us to systematically examine penetrance of all identified alleles. With the exception of c.1103G>A (p.R368H), previously reported pathogenic mutations were highly penetrant (91.2%). We conclude from the very low penetrance and genetic epidemiological analyses that c.1103G>A (p.R368H) is unlikely to be a disease-causing recessive mutation in congenital glaucoma as previously reported. All cases that lacked biallelic CYP1B1 mutations underwent whole exome sequencing. No mutations in LTBP2, MYOC or TEK were encountered. On the other hand, mutations were identified in genes linked to other ophthalmic phenotypes, some inclusive of glaucoma, highlighting conditions that might phenotypically overlap with primary congenital glaucoma (SLC4A4, SLC4A11, CPAMD8, and KERA). We also encountered candidate causal variants in genes not previously linked to human diseases: BCO2, TULP2, and DGKQ. Our results both expand and refine the genetic spectrum of congenital glaucoma with important clinical implications.
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Acknowledgements
We thank the study families for their enthusiastic participation. We also thank the Sequencing and Genotyping Core Facilities at KFSHRC for their technical help. This work was funded in part by KACST 15-BIO3688-20 (FSA), the Saudi Human Genome Program (King Abdulaziz City for Sciences and Technology) (FSA), and King Salman Center for Disability Research (FSA).
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Figure S1.
Distribution of two CYP1B1 mutations, c.182G > A (p.G61E) and c.1103G > A (p.R368H), within the Saudi Genome Program population and Glaucoma datasets. MAF in 2363 Saudis who are part of the Saudi Human Genome Program is comparable for the two alleles. However, their distribution in the glaucoma cohort shows marked deviation with significant enrichment only for c.182G > A (p.G61E) but not c.1103G > A (p.R368H) (PDF 338 kb)
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Alsaif, H.S., Khan, A.O., Patel, N. et al. Congenital glaucoma and CYP1B1: an old story revisited. Hum Genet 138, 1043–1049 (2019). https://doi.org/10.1007/s00439-018-1878-z
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DOI: https://doi.org/10.1007/s00439-018-1878-z