Dissection Of Quantitative Endophenotypes For Glaucoma In MYOC Mutant Carriers

Abstract

Purpose: : To understand the polygenic nature of primary open-angle glaucoma, we are searching for modifier genes that account for variable expressivity of the disorder in families in which MYOC has been identified as the disease-causing gene. To establish a reliable classification system of severity for the disease, we dissected the quantitative endophenotypes displayed by heterozygotes carrying the myocilin K423E mutation.

Methods: : The French-Canadian autosomal dominant glaucoma CA family (600 members) has been followed up since the 1950s. Complete records of 150 CA MYOC^K423E heterozygotes were reviewed to extract the values of quantitative variables for: 1. age at onset (AAO), 2. maximal intraocular pressures before treatment (Max IOP), 3. maximal IOP after beginning of treatment (Max IOP under Rx), 4. optic nerve degeneration measured as cup-to-disk ratio (C/D) and, 5. progression of optic nerve degeneration measured as the variation of ratios divided by the time period between 2 C/D ratios (ΔC/D per year).

Results: : AAO ranged from 7 to 63 years old with 17 % of the men showing onset < 20 as compared to 13 % of the women. Max IOP were classified in 3 categories, with 100 heterozygotes classified in the high severity group with Max IOP ≥ 27, 11 carriers in the moderate group with Max IOP between 22 and 27 and 35 heterozygotes in the low severity group with Max IOP < 22 mm Hg. Of the 104 treated carriers, 80 were categorized in the high severity group with Max IOP under Rx ≥ 22 mm Hg, whereas 13 of them were in the low severity category with Max IOP under Rx below 22. C/D were measured in 144 carriers, 58 were classified in the severe category with C/D ≥ 0.8, 10 in the moderate with C/D between 0.7 and 0.8, and 76 in the low category with C/D < 0.7. When ΔC/D per year was evaluated in 142 carriers, 3 groups were defined, with 70 carriers in the low severity group < 0.02, i.e. a variation of < 0.2 C/D over 10 years, 18 as moderate, from 0.02 to 0.03, and 43 as high with a ΔC/D per year ≥ 0.03.

Conclusions: : Dissection of endophenotypes was critical for establishing a reliable classification system for severity of glaucoma. To facilitate our understanding of the polygenic nature of glaucoma, this system is now used to analyze the dependency between the different endophenotypes during the progression of the disease.

Keywords: genetics • gene modifiers • clinical (human) or epidemiologic studies: risk factor assessment