Assessment of a race-specific normative HRT-III database to differentiate glaucomatous from normal eyes.

PURPOSE: To determine if a new, normative, race-specific database enhances the ability of confocal scanning laser ophthalmoscopy to differentiate normal from glaucomatous eyes. METHODS: One eye of eligible normal and glaucoma patients was enrolled. All subjects underwent a complete ophthalmologic examination, standard achromatic perimetry (SITA-SAP, 24-2), and confocal scanning laser ophthalmoscopy [Heidelberg retinal tomograph (HRT-II)] within 1 month of enrollment. Racial groups were defined by self-report. Glaucoma was defined by the existence of reproducible SAP loss (pattern standard deviation <5% and/or Glaucoma Hemifield Test outside normal limits) on 2 consecutive fields. Normal subjects had 2 normal visual fields (pattern standard deviation >5% and Glaucoma Hemifield Test within 97% normal limits) and a normal clinical examination. HRT-II examinations were exported to the HRT-III software, which includes a large race-specific normative database consisting of 733 white and 215 black eyes. Moorfields regression analysis (MRA) for the most abnormal optic disc sector was compared between the HRT-II (MRA2) and the HRT-III software before (MRA3-B) and after (MRA3-A) adjustment for race. Sectors outside the 99.9% confidence interval limits ("outside normal limits") were determined to be abnormal. RESULTS: We enrolled 124 black (52 glaucoma, 72 normal) and 96 white (32 glaucoma, 64 normal) subjects. Mean age was 51+/-13 years and 50+/-16 years for blacks and whites, respectively (P = 0.45). Visual field mean deviation was -7.3+/-6.7 db for glaucomatous eyes and -0.4+/-1.1 db for normal eyes (P < 0.001). Sensitivity and specificity for the HRT-II was 71.9% and 95.3%, respectively, for white subjects and 50.0% and 98.6%, respectively, for black subjects. Using the expanded HRT-III database, analysis yielded a sensitivity of 81.3% and specificity of 93.8% for whites and a sensitivity of 71.2% and specificity of 86.1% for blacks. After an adjustment for black ethnicity was made in the HRT-III program, the sensitivity and specificity for blacks was 65.4% and 90.3%, respectively. CONCLUSIONS: A new, larger, race-specific HRT-III database increases sensitivity while maintaining specificity for whites and increases sensitivity but decreases specificity for blacks. New software and databases based on race require careful scrutiny before use in clinical practice.

Identification of a novel adult-onset primary open-angle glaucoma (POAG) gene on 5q22.1.

Glaucoma is a leading cause of blindness in virtually every country. Development of an accurate diagnostic test for presymptomatic detection of individuals at risk is an urgent requisition for this condition. Herein, we report mapping of a new adult-onset primary open-angle glaucoma (POAG) locus on 5q22.1 (GLC1G) and identification of its defective gene. Mutation screening of seven candidate genes from the GLC1G critical region (approximately 2 Mb between D5S1466 and D5S2051) identified only one significant alteration in the WDR36 (WD40-repeat 36) gene. This mutation (i.e. D658G) was segregated in all affected members of our first GLC1G-linked family but it was absent in 476 normal control chromosomes. Further screening of WDR36 in a total of 130 POAG families revealed 24 DNA variations. Overall, four mutations (N355S, A449T, R529Q and D658G) were identified in 17 (5.02-6.92%) unrelated POAG subjects, 11 with high-pressure and six with low-pressure glaucoma. These mutations were absent in a minimum of 200 normal control chromosomes and, further they were conserved between WDR36 orthologues in mouse, rat, dog, chimp and human. WDR36 is a novel gene with 23 exons, which encodes for 951 amino acids and a protein with multiple G-beta WD40 repeats. By northern blotting, two distinct mRNA transcripts of 5.9 and 2.5 kb were observed in human heart, placenta, liver, skeletal muscle, kidney and pancreas. WDR36 gene expression in lens, iris, sclera, ciliary muscles, ciliary body, trabecular meshwork, retina and optic nerve were established by RT-PCR. In mouse, two transcripts of 3.5 and 2.9 kb showed analogous expression patterns to human. mRNA expressions were detected in 7-, 11-, 15- and 17-day-old developing mouse embryos. In summary, WDR36 is a novel causative gene for adult-onset POAG at the GLC1G locus. Specific ocular expressions and observed mutations are consistent with WDR36 role in etiology of both high- and low-pressure glaucoma.