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Abstract #18547 Published in IGR 3-3
Evidence for genetic heterogeneity within eight glaucoma families, with the GLC1A Gln368STOP mutation being an important phenotypic modifier
Craig JE; Baird PN; Healey DL; McNaught AI; McCartney PJ; Rait JL; Dickinson JL; Roe L; Fingert JH; Stone EMOphthalmology 2001; 108: 1607-1620
OBJECTIVE: To investigate the phenotype and age-related penetrance of primary open-angle glaucoma (POAG) in Australian families with the most common myocilin mutation (Gln368STOP). DESIGN: Cross-sectional genetic study. PARTICIPANTS: Eight pedigrees carrying the Gln368STOP mutation were ascertained from 1730 consecutive cases of POAG in the Glaucoma Inheritance Study in Tasmania. METHODS: Index cases and available family members were examined for signs of glaucoma, and the presence of the GLC1A Gln368STOP mutation was ascertained by single-strand conformation polymorphism analysis and subsequent direct sequencing. RESULTS: From the eight pedigrees, 29 Gln368STOP mutation-carrying individuals with either ocular hypertension (OHT) or POAG were found, with a mean age at diagnosis of 52.4 ± 12.9 years and a mean peak intraocular pressure (IOP) of 28.4 ± 4.7 mmHg. A further 11 mutation carriers older than 40 years were studied, who as yet show no signs of OHT or POAG. Within the eight pedigrees, a further 31 individuals with OHT or POAG were identified who did not carry the Gln368STOP mutation. For these individuals, the mean age at diagnosis was higher (62.3 ± 13.7 years, p < 0.01), and the mean peak IOP lower (25.4 ± 6.4 mmHg, p = 0.01). For Gln368STOP carriers, age-related penetrance for OHT or POAG was 72% at the age of 40 years and 82% at 65 years. A positive family history of POAG was present in all index cases. Five of the eight pedigrees had a positive family history on both maternal and paternal sides. Seven of the eight pedigrees had one or more individuals with POAG who did not carry the mutation. Eight of the 28 Gln368STOP carriers with OHT or POAG had undergone trabeculectomy. CONCLUSIONS: The GLC1A Gln368STOP mutation is associated with POAG, which in the pedigrees studied is of a younger age of onset and higher peak IOP than non-mutation glaucoma cases. In addition, Gln368STOP mutation glaucoma cases were more likely to have undergone glaucoma drainage surgery. The authors did not observe simple autosomal dominant inheritance patterns for POAG in these pedigrees. Other factors, as yet uncharacterized, are involved in expression of the POAG phenotype in Gln368STOP pedigrees.
Dr D.A. Mackey, Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, 32 Gisborne Street, East Melbourne, Victoria, Australia 3002
Classification:
1.2 Population genetics (Part of: 1 General aspects)