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V. Raymond, P. Belleau, K. Lebel, R. Arseneault, J.-L. Anctil, A. Duchesne, G. Côté, M.-A. Rodrigue, Quebec Glaucoma Network; Evidence for Modifier Gene(s)/Loci Altering Glaucoma Severity in a Huge French-Canadian Myocilin Family. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4034.
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We reported that autosomal dominant open-angle glaucoma (OAG) in the huge French-Canadian CA family was caused by the Lys423Glu myocilin mutation. The mutation led to glaucoma in children as well as in old adults. We hypothesized that this wide phenotypic variability may be caused by modifier gene(s), or loci, interacting with the primary disease-causing mutation. As a 1st step towards its/their characterization, we assessed if sub-phenotypes for the disorder clustered in particular branches of the pedigree.
Of the 709 individuals studied, 145 were heterozygotic carriers. Complete ophthalmologic records were obtained for 132 of them. As intraocular hypertension (OHT) always preceded OAG, age at onset (AAO) was defined as age at which OHT or OAG was first detected.
Eighty five (85) carriers were diagnosed OAG or OHT with treatment (respectively, 51 and 34), 9 were OHT while the other 38 carriers were still asymptomatic. AAO varied from 7 to 63 years old with a mean at 28. Penetrance of the mutation was 75% in carriers aged 35 and older. 42% of the carriers were diagnosed under 25 years of age, 28% between 26 and 34 and 30% above 35. We defined the neighborhood of each carrier as a set of pedigree members in which the kingship coefficient between the carrier and other members was equal or above 0.0625. For each heterozygote, we calculated the median of age at onset for this carrier's neighborhood. Each heterozygote was then classified into 3 groups of age according to this median: equal or below 25 years of age, between 26 and 33, and, 34 or above. Using this procedure, we observed 5 distinct clusters relative to AAO. Clusters 1, 2 and 3 comprised 52 heterozygotes. Almost all showed a neighborhood median for AAO at 34 years of age or above. In clusters 4 and 5, this median was at 25 years of age or less. In each cluster, descendants originated from 1 distinct ancestor. We further observed that progression of optic disk damage (measured as the mean of cup/disk ratio) within the same age group was more severe in patients with AAO under 30.
Within the CA pedigree, age at onset was a very good predicator of glaucoma severity. Our investigation clearly showed that heterozygotes for the Lys423Glu myocilin mutation clustered into large groups with extreme ages at onset for the glaucoma phenotype. This study supports the presence of at least 1 modifier gene, or locus, that alters glaucoma severity caused by the Lys423Glu myocilin mutation. This modifier may interact with other myocilin mutations.
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