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Purpose: Glaucoma is a major cause of visual impairment and blindness in developed countries. Half of those with glaucoma are unaware that they have the disease. Mutations in the myocilin (MYOC) gene are responsible for 3 to 5% of primary open angle glaucoma, thus predictive DNA testing in family members of some glaucoma pedigrees is possible. We wished to determine the attitudes of affected and unaffected family members to the use of predictive DNA testing in glaucoma., Subjects and Methods: We surveyed the attitudes of family members from one such pedigree to determine the acceptability of predictive DNA testing. We studied 72 members of a large family in which the MYOC mutation, THR377MET, segregates. Family members were examined over an 8-year period as part of research initiated to identify the gene. Once the mutation was identified, we offered participants the result of their DNA test after a genetic counseling session. Family members were subsequently given a questionnaire about the counseling and DNA result., Results: Most wished to know their result after counseling; 26 of 27 (96%) felt the genetic counseling session was necessary, but participants' attitudes varied as to whether they preferred this in person, by phone, or letter. Forty three patients were resurveyed 5 years after their initial counseling session. No adverse problems relating to the predictive testing were reported, though two had been asked about DNA testing by insurance companies; 5 of 24 (21%) individuals who had been informed they did not carry the mutation were unsure if they carried the mutation 5 years after counseling, while all 19 mutation carriers (who were being examined annually) correctly recalled their mutation status., Conclusions: This study suggests that predictive glaucoma testing in appropriate circumstances is acceptable to patients and their families.

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.

A glaucoma locus, GLC1A, was identified previously on chromosome 1q. A gene within this locus (encoding the protein myocilin) subsequently was shown to harbor mutations in 2-4% of primary open angle glaucoma patients. A total of 1703 patients was screened from five different populations representing three racial groups. There were 1284 patients from primarily Caucasian populations in Iowa (727), Australia (390) and Canada (167). A group of 312 African American patients was from New York City and 107 Asian patients from Japan. Overall, 61 different myocilin sequence variations were identified. Of the 61 variations, 21 were judged to be probable disease-causing mutations. The number of probands found to harbor such mutations in each population was: Iowa 31/727 (4.3%), African Americans from New York City 8/312 (2.6%), Japan 3/107 (2.8%), Canada 5/167 (3.0%), Australia 11/390 (2.8%) and overall 58/1703 (3. 4%). Overall, 16 (76%) of 21 mutations were found in only one population. The most common mutation observed, Gln368Stop, was found in 27/1703 (1.6%) glaucoma probands and was found at least once in all groups except the Japanese. Studies of genetic markers flanking the myocilin gene suggest that most cases of the Gln368Stop mutations are descended from a common founder. Although the specific mutations found in each of the five populations were different, the overall frequency of myocilin mutations was similar ( approximately 2-4%) in all populations, suggesting that the increased rate of glaucoma in African Americans is not due to a higher prevalence of myocilin mutations.