title: Demonstration of a founder effect and fine mapping of dominant optic atrophy locus on 3q28-qter by linkage disequilibrium method: a study of 38 British Isles pedigrees.
abstract: Dominant optic atrophy, a hereditary optic neuropathy causing decreased visual acuity, colour vision deficits, a centro-caecal scotoma and optic nerve pallor, has been mapped to a genetic interval of 1.4 cM between loci D3S3669 and D3S3562 on chromosome 3q28-qter. In order to further refine the critical disease interval, and to test the power of haplotype analysis and linkage disequilibrium mapping, we identified a total of 38 families with dominant optic atrophy, unrelated on the basis of genealogy, from a data base of genetic eye disease families originating from the British Isles. They were studied with 12 highly polymorphic microsatellite markers spanning a region of 12 cM around the dominant optic atrophy locus (OPA1). Allelic frequency analysis [chi-squared test, likelihood ratio test (LRT) and P values] and haplotype parsimony analysis showed evidence of a founder effect in 36 of the 38 pedigrees. Six markers (D3S3669, D3S1523, D3S3642, D3S2305, D3S3590 and D3S3562), spanning 1.4 cM across the disease-associated region, demonstrated significant linkage disequilibrium by LRT (P < 0.05). A peak LRT value of 10.86 (P < 0.0005, lambda = 0.4) occurred at D3S3669. On linkage disequilibrium multipoint analysis the maximum lod score of 8.01 is achieved at D3S1523, and 95% confidence intervals suggest that OPA1 lies within ca. 400 kb of D3S1523.
authors.affiliation: Department of Molecular Genetics, Institute of Ophthalmology, London, UK. mvotruba@hgmp.mrc.ac.uk
authors.forename: M
authors.initials: M
authors.lastname: Votruba
authors.forename: A T
authors.initials: AT
authors.lastname: Moore
authors.forename: S S
authors.initials: SS
authors.lastname: Bhattacharya
mesh_terms: D000483:Alleles; D002874:Chromosome Mapping; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D005787:Gene Frequency; D005799:Genes, Dominant; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics*; D008297:Male; D015418:Optic Atrophies, Hereditary / Q000235:genetics*; D010375:Pedigree; D006113:United Kingdom