Complete form of X-linked congenital stationary night blindness: Refined mapping and evidence of genetic homogeneity

A number of distinct, partly non-overlapping genetic loci have been reporte d for the complete type of X-Iinked congenital stationary night blindness ( CSNB1), suggesting genetic heterogeneity. In order to refine the localizati on of the CSNB1 gene and to demonstrate genetic homogeneity, linkage analys is was performed in two large CSNB1 families. Clinical features consistent with the diagnosis of CSNB1 were documented in five patients from a German seven-generation kindred by full ophthalmological examination including psy chophysical and electroretinographical testing. Haplotype analysis in 30 me mbers of the large German family was performed with 38 polymorphic markers predominantly covering the critical region. Linkage analyses defined a locu s for CSNB1 with flanking markers DXS8042 and DXS228, refining the interval to 2.5 cM in Xp11.4. In addition, two-point linkage analysis was carried o ut using the MLINK computer program. In agreement with meiotic breakpoints, lod scores of 3.0 and greater were obtained for markers located to the pro ximal site of the former 5 cM CSNB consensus interval. A large Dutch CSNB1 family was re-evaluated with markers from the Xp11.4 region, and supports t he CSNB1 minimal interval found in the German family. Together with previou s results from three unrelated families from Sweden, Sardinia and Great Bri tain, our results provide evidence of genetic homogeneity in the disorder. Subsequent-mutation analyses in CSNB1 patients revealed no pathogenic seque nce alterations in DFFRX and CASK genes, but retain candidates for other di seases mapping to that region.