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A. L. Vincent, H. Patel, A. E. Richards, B. De Karolyi, S. J. Best, H. V. Danesh-Meyer; Molecular Screening of Glaucoma Genes in Adult Glaucoma Supports the Role of CYP1B1 in Non-Congenital Glaucoma Phenotypes. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2160.
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Despite an increasing knowledge of the genetic pathophysiology of glaucoma, mutations in known or suspected genes account for less than 10% of all disease.The majority of patients remain without molecular characterisation, as gene screening predominantly remains a research tool rather than an essential part of the clinical work-up. Over 30% of patients have a positive family history. Many previous studies examined genetic variation in well defined populations of specific glaucoma phenotypes. We aimed to determine the mutational spectrum and frequency in the genes implicated in glaucoma, in a range of participants from glaucoma subspecialty clinics - the only requirement being a positive family history.
115 patients were recruited from Glaucoma clinics (hospital and private).All probands reported a history of at least one affected family member. The proband’s diagnosis ranged from glaucoma suspect, OHT, PXF and POAG. Collected DNA samples were screened for mutations in all coding exons of MYOC and CYP1B1, as well as OPTN (exons 4,5 and16) and WDR36 (exons 1,4,5,11,13,17). Cascade screening of affected family members was undertaken where possible.
6/115 (3.5%) of individuals had at least one pathogenic or hypomorphic CYP1B1 allele, and included one compound heterozygote. Two individuals also carried a sequence variation in OPTN or WDR36 which have somewhat controversially been implicated in POAG. Two mutations are previously unreported - p.Ser6Gly, and p.Val243 Leu. The phenotype associated with these pathogenic alleles are; Glaucoma suspect with Meesman dystrophy, POAG(4), and Pseudoexfoliative glaucoma. The only MYOC change of any significance was the Lys398Arg change (n=2, 1.7%) of questionable pathogenicity.
Mutational analysis of known or associated glaucoma genes in a mixed glaucoma population replicates the frequency of pathogenic or hypomorphic CYP1B1 changes demonstrated in other series. Heterozygous changes in CYP1B1 occurred at a greater frequency than any other of the implicated genes confirming its contribution to the pathogenesis of a range of glaucoma phenotypes. Therefore CYP1B1 should be considered an essential part of the mutational workup of a glaucoma population.
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