Haplotype analysis of the USH1D locus and genotype-phenotype correlations

Usher syndrome (USH) is characterised by hearing impairment and progressive pigmentary retinopathy. USH can be divided into three subtypes based on th e severity and progression of the major clinical findings. These subtypes a re genetically heterogeneous, with at least six loci for USH1, three for US H2 and one for USH3. In the present study, five unrelated consanguineous fa milies with USH I were analysed I for linkage to markers flanking the six U SH1 loci. Two of these families, one Pakistani and one Turkish, demonstrate d linkage to the USH1D locus. In another family, haplotype segregation was consistent with linkage to USH1C. The remaining families were not linked to any of the six USH I loci, providing support for the existence of at least one additional USH I locus. Analysis of these two new USH1D families allow ed us to narrow the USH1D candidate region to a 7.3-cM interval with a telo meric flanking marker at D10S1752. Comparison of the affected haplotypes in our Pakistani family with the original Pakistani USH1D family yielded no e vidence for a founder effect. The identification of two additional affected families suggests that the USH1D may be a more common form of USH1 than or iginally suspected. The USH1D (CDH23) gene has recently been cloned. Mutati on analysis has shown two different CDH23 mutations in the two Pakistani US H1D families studied, which confirmed our finding that there was no evidenc e for a founder effect by haplotype analysis. The interesting correlations between genotype and phenotype in CDH23 are also summarised.