Autosomal dominant macular dystrophy in a large Canadian family

Background: We studied a large Canadian family (178 total family members) spanning seven generations with autosomal dominant macular dystrophy. We performed a study to identify the gene mutation responsible for the disease in the family. Methods: Participating family members were evaluated clinically. Genetic linkage, genotyping, mutation screening and an extensive genealogic investigation were performed. Results: The common clinical findings in affected family members included progressive early- to mid-onset visual loss and extensive areas of central chorioretinal atrophy. Two-point linkage analysis indicated linkage to chromosome bp. Direct DNA sequencing showed a C/T transition in codon 172 of the retinal degeneration slow (RDS) gene creating an amino acid change to Arg 172Trp. Haplotype analysis of affected family members using microsatellite markers distributed around the RDS gene locus revealed that the markers were not conserved when compared to members of British families with the Arg 172Trp mutation. Genealogic studies indicated the family immigrated to Canada from Ireland in 1843. Interpretation: A newly identified large family with autosomal dominant macular dystrophy is described. The phenotypic appearance of the fundus is similar to that of previously described patients with an Arg 172Trp mutation in the RDS gene. Haplotype analysis of markers spanning the disease locus identified a new founder for this mutation. The identification of the disease-causing gene in this family allows for better genetic counselling for patients with this condition and provides a basis to distinguish clinically similar types of macular dystrophy based on the clinical phenotype.