Clinical and genetic characterization of a Danish family with North Carolina macular dystrophy

PURPOSE: To describe the phenotype of a family with an autosomal dominant macular dystrophy and identify the chromosomal location of the gene that causes this phenotype. METHODS: Twelve members of a three-generation family underwent routine clinical examination, including fundus photography. Four of the patients underwent extended examination with Goldmann perimetry, full-field electroretinogram, dark adaptation, and color vision testing, and two patients underwent optical coherence tomography and fundus autofluorescence examination. DNA samples were obtained from 12 family members and 3 spouses and genotyped at the known North Carolina Macular Dystrophy (NCMD) locus on chromosome 6q (MCDR1: OMIM 136550) using short tandem repeat polymorphisms. DNA samples were subsequently examined with a genome-wide scan of single nucleotide polymorphisms and the genotypes that were produced were studied with linkage and haplotype analyses. RESULTS: The 10 affected family members had clinical findings of macular lesions that are typical for NCMD. The small drusen-like yellowish lesions of mild NCMD were hyperautofluorescent. Hyperpigmented foveal lesions were surrounded by a zone of confluent hyperautofluorescence. Linkage analysis of short tandem repeat polymorphism genetic markers excluded the NCMD locus on chromosome 6. However, analysis of single nucleotide polymorphism genotypes from a genome-wide scan showed that NCMD in our pedigree is linked to a region on chromosome 5p that overlaps the previously mapped macular dystrophy (MCDR3) locus with a maximum log of the odds (LOD) score of 2.69 at a recombination fraction of 0.00 (markers D5S406, D5S1987, and D5S2505). DISCUSSION: We report the first pedigree with NCMD from Scandinavia, and the first confirmation that a gene for this condition is located on chromosome 5p13-p15. The bright elements or lesions typical of NCMD differed from drusen in that no sign of accumulation of material between the retinal pigment epithelium and Bruch’s membrane was seen. While the present study has found indications that the elements are located in the outermost layers of the retina, their precise location remains to be identified directly.