How significant is a family history of glaucoma? Experience from the Glaucoma Inheritance Study in Tasmania.

PURPOSE: To determine what proportion of primary open angle glaucoma (POAG) in Tasmania, Australia is familial. METHODS: Between 1994 and 1996 an audit of Tasmanian patients diagnosed with glaucoma was performed. Identified probands along with their family members were invited to participate. Family history of POAG was noted and pedigrees constructed. Each participant underwent a detailed examination, including visual acuity, intraocular pressure measurement, gonioscopy, optic disc assessment and visual field testing. Participants were classified as normal, suspect or POAG. Data from 467 participants in the Twins Eye Study in Tasmania (TEST) were used as a reference for the general population. RESULTS: Of 2062 participants examined, 1700 were classified as POAG. A total of 1014 participants (59.6%) belonged to families in which other members were affected (familial glaucoma). Six hundred and fifty-six of these 1014 familial cases (64.8%) had a first-degree relative affected. The number of affected members in the family groups varied from two to 29. Six hundred and eighty-eight participants had no known family history of POAG (sporadic glaucoma). There were significantly more POAG patients with a family history of POAG compared to the TEST population (chi2 = 161.81, P < 0.0001), and for a person with POAG the odds ratio of having a positive family history was 4.1 (95% confidence interval: 3.2-5.2). CONCLUSION: Approximately 60% of POAG in Tasmania is familial. This percentage is higher than most previous reports of familial glaucoma and emphasizes the importance of genetics in POAG, with major implications for screening and future research.

Glaucoma phenotype in pedigrees with the myocilin Thr377Met mutation.

OBJECTIVE: To investigate the phenotype and age-related penetrance of primary open-angle glaucoma (POAG) in Australian families with the myocilin mutation Thr377Met. METHOD AND DESIGN: Cross-sectional genetic study. Four unrelated pedigrees carrying the Thr377Met mutation were ascertained from more than 2000 consecutive cases of POAG in the Glaucoma Inheritance Study in Tasmania and from families with glaucoma referred to the study from throughout Australia. Index cases and available family members were examined for signs of glaucoma, and the presence of the GLC1A Thr377Met mutation was ascertained by single-strand conformation polymorphism analysis and subsequent direct sequencing. RESULTS: From the 4 pedigrees carrying the Thr377Met mutation, 23 individuals with either ocular hypertension (OHT) or POAG were found, with a mean +/- SD age at diagnosis of 41.2 +/- 11.5 years, and a mean peak intraocular pressure of 31.7 +/- 9.9 mm Hg. A further 9 mutation carriers older than 18 years were studied who as yet showed no signs of OHT or POAG (6 of these 9 were younger than 30 years). A single individual with POAG was identified who did not carry the Thr377Met mutation. For Thr377Met carriers, age-related penetrance for OHT or POAG was 88% at age 30 years. A positive family history of POAG was present for 3 of the 4 index cases. Thirteen (57%) of the 23 Thr377Met carriers with OHT or POAG had undergone glaucoma drainage surgery. Although the glaucoma in these families appears to be pressure dependent, 2 individuals showed optic disc cupping before detected elevation in intraocular pressure. One family was of British origin, with a different background haplotype from the other 3 families from Greece or Macedonia, who shared a common haplotype. CONCLUSIONS: The GLC1A Thr377Met mutation is associated with POAG that, in the pedigrees studied, had a younger age at onset and higher peak intraocular pressure than in pedigrees with the more common Gln368STOP mutation. In addition, patients with glaucoma with the Thr377Met mutation were more likely to have undergone glaucoma drainage surgery.