North Carolina macular dystrophy: clinical features, genealogy, and genetic linkage analysis.

PURPOSE

To study the North Carolina macular dystrophy phenotype (MCDR1) in multiple families of different ethnic backgrounds, to determine the genetic relationships of these families, and to determine the minimal candidate region of the MCDR1 gene.

METHODS

Thirteen families with the North Carolina MCDR1 were ascertained. These families were of various ethnic and geographic origins, such as Caucasian, Mayan Indian, African American, French, British, German, and American. Extensive genealogical investigations were performed for all families. A total of 232 members of these families underwent comprehensive ophthalmic examinations, including blood collection for genotyping. Of these, 117 were found to be affected with the disorder. Genetic linkage simulation studies were performed using the computer program SIMLINK. Two-point linkage analysis, haplotype analysis, and multipoint linkage analyses were performed using the computer programs M-LINK, VITESSE, and FASTLINK.

RESULTS

The clinical features were consistent with the diagnosis of North Carolina macular dystrophy in all families studied. Multipoint linkage analysis and haplotype analysis indicate that the MCDR1 gene is in the 1.1-centimorgan (cM) interval between the genetic markers D6D249 and D6S1671, with a maximum LOD score of 40.03. There was no evidence of genetic heterogeneity. Families 765, 768, 772, 1193, and 1292 shared the same chromosomal haplotype in this region, suggesting they are the result of the same ancestral mutation. The remaining families each likely represent independent origins of the mutation in the MCDR1 gene. North Carolina macular dystrophy is present worldwide and does not emanate from a single founder from North Carolina.