Screening Glaucoma Genes in Adult Glaucoma suggests a multiallelic contribution of CYP1B1 to Open Angle Glaucoma Phenotypes.

Abstract

Background: Despite increasing knowledge of the genetic pathophysiology of glaucoma, mutations in known genes account for less than 15% of disease. Gene screening predominantly remains a research tool rather than an essential part of the clinical work-up. We aimed to determine the mutational spectrum and frequency in the genes implicated in glaucoma, in a range of glaucoma and "glaucoma suspect" participants, with a positive family history. Methods: Observational large case-series. 115 patients recruited from public hospital and private clinics had diagnoses of glaucoma suspect (GS), ocular hypertension (OHT), Pseudoexfoliative glaucoma (PXG) or primary open angle glaucoma (POAG and at least one affected family member. In a University laboratory, DNA samples were screened for mutations in all coding exons of MYOC and CYP1B1, and OPTN (exons 4, 5 and 16). WDR36 (exons 1,4,5,8,11,13,17) was screened in those with CYP1B1 changes.LOXL1 risk variants were screened in PXG pedigrees. Cascade screening of family members was undertaken. Results: 7/115 (6.1%) of individuals had at least one pathogenic or hypomorphic CYP1B1 allele associated with GS, POAG (5), and PXG phenotypes, including two novel sequence variations (p.Ser6Gly, p.Val243Leu). No pathogenic MYOC change was detected. Five individuals (4.3%) carried a OPTN sequence variation. 3 of the 7 with CYP1B1 changes had polygenic changes. Conclusions: Mutational analysis of known glaucoma genes in a mixed glaucoma population replicates the reported frequency of pathogenic CYP1B1 changes. Heterozygous CYP1B1 changes occurred at a greater frequency than other genes. Glaucoma pathogenesis in the clinic setting is genetically heterogeneous and may be polygenic.