Prevalence of optineurin sequence variants in adult primary open angle glaucoma: implications for diagnostic testing.

Glaucoma, the leading cause of irreversible blindness world wide, affecting about 70 million people, 2 is characterised by progressive loss of optic nerve axons and visual field damage. As the condition is insidious, the diagnosis is often missed and the disease detected only later when patients have severe and irreversible visual impairment. Adult primary open angle glaucoma (POAG) is a major form of glaucoma world wide. Most POAG in white and AfroCaribbean populations is of the high tension glaucoma (HTG) type, with raised intraocular pressure (IOP) being a major contributory factor for visual loss. Normal tension glaucoma (NTG) is another important subtype of POAG in which typical glaucomatous cupping of the optic nerve head and visual field loss are present, but IOPs are consistently within the statistically normal population range. This accounts for about a third of all patients with POAG. Although the proportion of cases of glaucoma with a genetic basis has not been precisely defined, an increasing body of evidence derived from a range of populations indicates that glaucoma has a substantial heritable basis. It has been estimated that 20%–60% of patients with the disease have a family history, and under-reporting of a family history has been well documented in glaucoma. In 1997, myocilin (MYOC, MIM 601652), located on chromosome 1q25, was the first POAG gene to be characterised and found to be mutated in patients with juvenile and adult onset POAG. Subsequent studies found that MYOC mutations account for fewer than 5% of cases of adult POAG, with lower frequencies of MYOC mutations in Chinese and Japanese populations compared to white populations. 18 Rezaie et al recently identified a second POAG gene, optineurin (OPTN, MIM 602432) in the GLC1E interval on chromosome 10p, and showed that variations in this gene predominantly resulted in NTG. The most common OPTN mutation, Glu50 →Lys (E50K) was identified in 13.5% of families, 18% of whom had high IOP. A second OPTN variant, Met98 →Lys (M98K) was identified in 13.6% of familial and sporadic cases of POAG compared to 2.1% of controls, making it a considerable risk associated genetic factor for glaucoma. Such prevalence rates could potentially make the E50K/M98K variants more frequent than the Gln368Stop MYOC mutation, the most common mutation found in POAG, identified in 1.6% of unrelated glaucoma probands. The purpose of this study was to determine the prevalence of these two OPTN sequence variants in a large cohort of unrelated British patients with adult onset POAG to assess the feasibility of developing diagnostic testing for these variants in patients with glaucoma.