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V. Raymond, K. Lebel, P. Belleau, R. Arseneault, J.-L. Anctil, G. Côté, M. Amyot, The Québec Glaucoma Network; WDR36: A Potential Modifier Gene Altering Glaucoma Severity in a Huge French-Canadian Myocilin Family. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5115.
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© ARVO (1962-2015); The Authors (2016-present)
Primary open-angle glaucoma (POAG) is a complex disorder. While myocilin(MYOC) mutations account for about 4 % of cases, contribution of WDR36 to glaucoma is less understood. In the French-Canadian CA family, the MYOCK423E mutation causes wide phenotypic variability of autosomal dominant glaucoma. We recently detected in the pedigree, several clusters distinct for age-at-onset (AAO) supporting the presence of at least 1 modifier gene which alters glaucoma expressivity. To assess if WDR36 was a modifier gene, we performed genotype/phenotype correlation studies in double variants carrying MYOCK423E plus 1 WDR36 variation.
Within the 709 members of the CA family, we reexamined the heterozygotes, affected or not. Newly recruited subjects were screened for MYOCK423E. 156 MYOCK423E heterozygotes were detected. Complete ophthalmologic records, some going back to the 1950s, were analyzed for 142 carriers; all of them were screened for WDR36 variations by sequencing.
95 carriers were diagnosed juvenile or adult-onset open-angle glaucoma, or ocular hypertension (OHT) with Rx; 19 OHT without Rx; while 28 were still asymptomatic. Penetrance was 78% in carriers 40 years old or older. Since OHT occured before optic nerve degeneration, AAO was defined as age at which OHT or POAG was first detected. AAO varied from 7 to 63 years old. Among the variations detected in WDR36, 6 were non-synonymous amino acid (AA) changes. After excluding I264V polymorphic subjects, 24 MYOCK423E heterozygotes were double variants as they carried 1 WDR36 AA change. To assess for an effect of WDR36 variations on AAO, we compared AAO of glaucoma in these double variants versus the median of AAO in MYOCK423E carriers who were WDR36wild-type and shared a kinship coefficient of ≥ 0,0625 with the double variants; ie MYOC heterozygotes, 1st degree cousin or closer, in the neighborhood of the double variants. 18 double variants were analyzed, 10 of these showed AAO younger than the median AAO of their neighborhood. Five others displayed a younger AAO, but their respective AAO was within the range of their median AAO. Interestingly, 4 double variants, all of them with the WDR36D658G variation, were diagnosed > 10 years younger than their median AAO.
WDR36 may contribute to the glaucoma phenotype as a modifier gene. Alternatively, a 2nd gene or locus, in linkage disequilibrium with WDR36, may act as a modifier of glaucoma severity in myocilin mutation carriers.
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