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

Dominant optic atrophy, a hereditary optic neuropathy causing decrease d visual acuity, colour vision deficits, a centro-caecal scotoma and o ptic nerve pallor, has been mapped to a genetic interval of 1.4 cM bet ween loci D3S3669 and D3S3562 on chromosome 3q28-qter. In order to fur ther refine the critical disease interval, and to test the power of ha plotype analysis and linkage disequilibrium mapping, we identified a t otal of 38 families with dominant optic atrophy, unrelated on the basi s of genealogy, from a data base of genetic eye disease families origi nating from the British Isles. They were studied with 12 highly polymo rphic microsatellite markers spanning a region of 12 cM around the dom inant optic atrophy locus (OPA1). Allelic frequency analysis [chi-squa red test, likelihood ratio test (LRT) and P values] and haplotype pars imony analysis showed evidence of a founder effect in 36 of the 38 ped igrees. Six markers (D3S3669, D3S1523, D3S3642, D3S2305, D3S3590 and D 3S3562), spanning 1.4 cM across the disease-associated region, demonst rated 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 lin kage 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.