Genome-wide association identifies ATOH7 as a major gene determining human optic disc size.

Optic nerve assessment is important for many blinding diseases, with cup-to-disc ratio (CDR) assessments commonly used in both diagnosis and progression monitoring of glaucoma patients. Optic disc, cup, rim area and CDR measurements all show substantial variation between human populations and high heritability estimates within populations. To identify loci underlying these quantitative traits, we performed a genome-wide association study in two Australian twin cohorts and identified rs3858145, P=6.2x10(-10), near the ATOH7 gene as associated with the mean disc area. ATOH7 is known from studies in model organisms to play a key role in retinal ganglion cell formation. The association with rs3858145 was replicated in a cohort of UK twins, with a meta-analysis of the combined data yielding P=3.4x10(-10). Imputation further increased the evidence for association for several SNPs in and around ATOH7 (P=1.3x10(-10) to 4.3x10(-11), top SNP rs1900004). The meta-analysis also provided suggestive evidence for association for the cup area at rs690037, P=1.5x10(-7), in the gene RFTN1. Direct sequencing of ATOH7 in 12 patients with optic nerve hypoplasia, one of the leading causes of blindness in children, revealed two novel non-synonymous mutations (Arg65Gly, Ala47Thr) which were not found in 90 unrelated controls (combined Fisher's exact P=0.0136). Furthermore, the Arg65Gly variant was found to have very low frequency (0.00066) in an additional set of 672 controls.

Outcome of peripheral iridotomy in subjects with uveitis.

BACKGROUND/AIMS: Peripheral iridotomy (PI) may be required in subjects with uveitis to manage iris bombe, seclusio pupillae and primary angle closure glaucoma. The aim of this study was to identify risk factors for failure of both laser and surgical PIs in patients with uveitis and determine survival durations. METHODS: Retrospective study of subjects with a history of uveitis undergoing yttrium-aluminium-garnet (YAG) laser or surgical PI at Auckland District Health Board over an 11-year period. Failure of PI was defined as loss of patency or recurrence of iris bombe. A mixed effects shared frailty model was constructed with PI nested within eyes nested within patients, to examine time to failure. RESULTS: 131 PIs were performed in 52 eyes of 39 subjects during the study period (111 YAG PIs and 20 surgical PIs). Median age at time of PI was 46.6 years and 60.5% of subjects were female. HLAB27 positive uveitis was the most common diagnosis (25.6% of subjects). Median survival time was 70 days for YAG PI and 11.0 years for surgical PI. On multivariate analysis, younger age at time of PI (HR 0.933, p<0.001) and iris bombe (HR 2.180, p=0.046) were associated with risk of failure. Surgical PI was associated with a lower risk of failure (HR 0.151, p<0.001) compared with YAG PI. Glaucoma developed in 19 eyes (36.5%), of which 13 required glaucoma surgery. CONCLUSION: Surgical PI had longer survival than YAG PI, and should be considered in subjects presenting with iris bombe and in young subjects with uveitis.

Primary open angle glaucoma in subjects harbouring the predicted GLC1L haplotype reveals a normotensive phenotype.

PURPOSE: Primary open angle glaucoma (POAG) is a complex heterogeneous disease. The aim of this study was to describe the POAG phenotype in individuals who harbour the novel GLC1L disease-associated haplotype in a large pedigree where the Myocilin Gln368STOP mutation also segregates. METHODS: The clinical findings from 24 subjects with POAG from the GTAS02 family recruited as part of the Glaucoma Inheritance Study of Tasmania (GIST) were compared relative to genotype status. The previously identified GLC1L disease haplotype encompasses a chromosomal region of 8.3 centimorgans bounded by the markers D3S3521 and D3S1289 on 3p21-22. RESULTS: In subjects with the GLC1L disease haplotype (with or without Gln368STOP), the POAG phenotype was characterized by a mean age at diagnosis of 54.3 years, and mean maximum recorded intraocular pressure (IOP) of 23.9 mmHg. The mean maximum recorded IOP was lower in subjects with the predicted disease haplotype and no Gln368STOP mutation, compared with subjects with the predicted disease haplotype and presence of the Gln368STOP mutation (P = 0.02). Presence of the Gln368STOP mutation was significantly more common in those with the predicted disease haplotype than those without (P = 0.04). In the four subjects carrying the GLC1L disease-associated haplotype without the Gln368STOP mutation, a normotensive glaucoma (mean maximum recorded IOP 15 mmHg, range 13-17 mmHg) was present. CONCLUSIONS: The GLC1L locus may be associated with glaucoma in the absence of elevated IOP. Discovery of the specific gene within the GLC1L locus on 3p21-22 would provide a useful addition to our ability to offer genetic testing and counselling to POAG individuals and their families.

The optic nerve head in myocilin glaucoma.

PURPOSE: Approximately 1 in 30 unselected patients with open-angle glaucoma (OAG) have a mutation in the myocilin gene. The purpose of this study was to describe the morphologic features of the optic nerve head (ONH) in myocilin glaucoma. METHODS: A case-control design was adopted. Sixty-six patients heterozygous for a range of myocilin mutation (cases) were matched in disease severity to 105 patients with OAG known not to have a myocilin mutation (controls), using visual field findings. Quantifiable analysis of the ONH was undertaken of stereoscopic photographs, by using custom software with a z-screen. Subjective grading of the cup depth, lamina cribrosa pore shape and orientation, and the slope of the neuroretinal rim was performed by an examiner masked to the subject's mutation status. Mutation screening was conducted using either direct sequencing or single-stranded conformation polymorphism analysis. RESULTS: Patients with a myocilin mutation had glaucoma diagnosed earlier (P < 0.001) and had higher maximum recorded intraocular pressures (P < 0.001) than did the control OAG subjects. There was no significant (P > 0.05) difference in global disc area, global neuroretinal rim area, alpha-parapapillary atrophy, beta-parapapillary atrophy, slope of neuroretinal rim, or visible lamina cribrosa morphology between myocilin mutation carriers and patients with nonmyocilin glaucoma. Disc hemorrhages were identified more frequently in those without mutations (14/209 vs. 1/129), though this was not significant after correction for multiple hypothesis testing. CONCLUSIONS: No major structural or morphologic difference of the ONH was detected in pooled data from subjects who had myocilin mutations compared with data from individuals with nonmyocilin glaucoma.

Heritable features of the optic disc: a novel twin method for determining genetic significance.

PURPOSE: Numerous genetic diseases and environmental stimuli affect optic nerve morphology. The purpose of this study was to identify the principal heritable components of visible optic nerve head structures in a population-based sample of twins. METHODS: Fifteen optic nerve specialists viewed stereoscopic optic nerve head photographs (Stereo Viewer-II; Pentax Corp., Tokyo, Japan) from 50 randomly selected monozygotic or dizygotic twin pairs. Before viewing, each expert was questioned about which optic nerve head traits they believed were inherited. After viewing a standardized teaching set, the experts indicated which twin pairs they thought were monozygotic. Participants were then questioned about how their decisions were reached. A rank-ordered Rasch analysis was used to determine the relative weighting and value applied to specific optic nerve head traits. RESULTS: The proportion of twin pairs for which zygosity was correctly identified ranged from 74% to 90% (median, 82%) across the panel. Experts who correctly identified the zygosity in more than 85% of cases placed most weighting on shape and size of the optic disc and cup, whereas experts with the lowest scores placed greater weighting on the optic nerve head vasculature in reaching their decisions. CONCLUSIONS: In determining the genetic components of the optic nerve head, the results of this study suggest that the shape and size of the optic disc and cup are more heritable and should receive a greater priority for quantification than should vascular features.

Screening for glaucomatous disc changes prior to diagnosis of glaucoma in myocilin pedigrees.

OBJECTIVE: To investigate whether structural differences of the optic nerve head are evident in young people who do not have manifest glaucoma but are known to carry myocilin mutations. METHODS: A case-control design was adopted. Subjects from Australian pedigrees known to have either the Gln368STOP myocilin mutation (cutoff age, <40 years) or the Thr377Met myocilin mutation (cutoff age, <30 years) were examined for signs of glaucoma. Stereoscopic disc photographs were digitalized. Analysis of the optic disc area, optic cup area, and neuroretinal rim area was performed using digital stereoscopy with a Z-screen. Mutation analysis was conducted using direct sequencing. The t test, corrected for multiple comparison testing, was used in analysis. RESULTS: A total of 29 myocilin mutation-carrying (case) and 33 mutation-free (control) individuals were reviewed. The mean +/- SD ages were 19.9 +/- 9.0 and 22.1 +/- 9.5 years in the mutation and mutation-free groups, respectively (P = .35). There was no significant difference in intraocular pressure between mutation carriers and noncarriers (P = .44). There were no statistically significant differences in the mean disc, neuroretinal rim, and cup areas between the groups. The mean +/- SD neuroretinal rim area was 1.24 +/- 0.24 mm(2) in the noncarrier group and 1.25 +/- 0.23 mm(2) in the mutation group (P = .46). No notch, nerve fiber layer defect, or neuroretinal rim hemorrhage was noted in any eye examined. CONCLUSIONS: Although confounded by penetrance and expressivity, no quantified structural difference in the optic nerve head was observed in individuals who had a myocilin mutation prior to the diagnosis of glaucoma.

Myocilin Gly252Arg mutation and glaucoma of intermediate severity in Caucasian individuals.

OBJECTIVE: To determine the phenotype of an Australian pedigree with the myocilin (MYOC) Gly252Arg mutation, comparing it with other pedigrees carrying the same mutation. METHODS: All recruited subjects underwent a comprehensive clinical examination, including optic disc assessment, applanation tonometry, and visual field measurement. Mutation analysis was performed through direct sequencing. Haplotype analysis was performed using microsatellite markers around the MYOC gene. RESULTS: Eight Gly252Arg mutation carriers with glaucoma were identified from the same pedigree. Carriers' mean +/- SD age at diagnosis was 46.3 +/- 11.4 years (range, 31-60 years). Highest recorded intraocular pressure ranged from 27 to 42 mm Hg (mean +/- SD, 32.4 +/- 5.6 mm Hg). Cup-disc ratios in the worst eye ranged from 0.6 to 0.9. Six of the 8 individuals had undergone filtration surgery. A common founding haplotype between MY5 and D1S218 was found for Caucasian individuals tested with this mutation. One subject was compound heterozygotic for the MYOC Gly252Arg mutation and a novel MYOC Gly244Val variant. CONCLUSIONS: Although a common founder for Gly252Arg across Caucasian subjects was found, the phenotype from this Australian MYOC mutation-carrying pedigree is less severe than previously described. The severity of glaucoma caused by the Gly252Arg mutation may be similar to the Thr377Met MYOC mutation, yet is more severe than the most common Gln368Stop mutation. CLINICAL RELEVANCE: Since its implication in glaucoma, much work has been performed investigating the clinical features of MYOC-related glaucoma. Given the strong genotype-phenotype correlations with MYOC disease-causing variants, health care professionals armed with such molecular information are able to accurately counsel patients on their likely disease course. Our work suggests that the disease associated with MYOC Gly252Arg is less severe than previously described in other pedigrees with this specific mutation.

A myocilin Gln368STOP homozygote does not exhibit a more severe glaucoma phenotype than heterozygous cases.

PURPOSE: To describe the phenotype of an individual homozygous for the common Gln368STOP myocilin mutation and to discuss the other family members. DESIGN: Cascade screening was performed for Australian families that had been identified as having the myocilin Gln368STOP mutation. METHODS: Recruited subjects underwent comprehensive clinical examination and mutation analysis for the Gln368STOP myocilin mutation by direct sequencing. RESULTS: One 49-year-old woman was found to be homozygous for the mutation. Her maximal recorded intraocular pressure was 17 mm Hg. Bilateral optic disk examination revealed small, healthy optic discs. Automated perimetry testing was normal. CONCLUSIONS: Neither the individual homozygous for the Gln368STOP myocilin mutation nor her younger heterozygous siblings displayed any signs suggestive of glaucoma. One of the two heterozygous parents did manifest glaucoma. Although there is the possibility of the homozygous individual developing glaucoma in the future, she does not manifest a phenotype that is more severe than usual.