CONGENITAL FIBROSIS OF THE EXTRAOCULAR-MUSCLES (AUTOSOMAL-DOMINANT CONGENITAL EXTERNAL OPHTHALMOPLEGIA) - GENETIC HOMOGENEITY, LINKAGE REFINEMENT, AND PHYSICAL MAPPING ON CHROMOSOME-12

Congenital fibrosis of the extraocular muscles (CFEOM) is an autosomal dominant syndrome of congenital external ophthalmoplegia and bilatera l ptosis. We previously reported linkage of this disorder in two unrel ated families to an 8-cM region near the centromere of human chromosom e 12. We now present refinement of linkage in the original two familie s, linkage analysis of five additional families, and a physical map of the critical region for the CFEOM gene. In each of the seven families the disease gene is linked to the pericentromeric region of chromosom e 12. D12S345, D12S59, D12S331, and D12S1048 do not recombine with the disease gene and have combined lod scores of 35.7, 35.6, 16.0, and 31 .4, respectively. AFM136xf6 and AFMb320wd9 flank the CFEOM locus, defi ning a critical region of 3 cM spanning the centromere of chromosome 1 2. These data support the concept that this may be a genetically homog eneous disorder. We also describe the generation of a YAC contig encom passing the critical region of the CFEOM locus. This interval has been assigned cytogenetically to 12p11.2-q12 and spans the centromere of c hromosome 12. These results provide the basis for further molecular an alyses of the structure and organization of the CFEOM locus and will h elp in the identification of candidate genes.