GENETIC-HETEROGENEITY OF USHER SYNDROME TYPE-II IN A DUTCH POPULATION

The Usher syndromes are a group of autosomal recessive disorders chara cterised by retinitis pigmentosa (RP) with congenital, stable (non-pro gressive) sensorineural hearing loss. Profound deafness, RP, and no ve stibular responses are features of Usher type I, whereas moderate to s evere hearing loss and RP with normal vestibular function describe Ush er type II. The gene responsible for most cases of Usher II, USH2a, is on chromosome 1q41; at least one other Usher II gene (as yet unlinked ) is known to exist. Usher III presents with a progressive hearing los s that can mimic the audiometric profile seen in Usher II. A gene caus ing Usher III in a group of Finnish families, USH3, resides on chromos ome 3q. Since the phenotypes for Usher II and III overlap, it is impor tant to determine how frequently Usher IIa, Usher IIb, and Usher III o ccur in a clinical population of non-Usher I patients. DNA was collect ed from 29 Dutch families and genotyped with six DNA markers known to flank the USH2a gene closely, and with five markers that flank USH3. R esults of haplotype and linkage analysis were consistent with linkage to the USH2a locus in 26 of these 29 Dutch families. Three families di splayed no linkage to 1q41 markers, and one of these three families ap peared unlinked to 3q markers as well; current haplotypes of the other two families are inconclusive for Linkage with the USH3 locus without further genotyping. While an A test for heterogeneity of USH2a was st atistically significant, no convincing evidence of linkage to USH3 was found in this Dutch sample. Consequently, the frequency of the unlink ed variety of Usher IIa (Usher nb) in The Netherlands was estimated as 0.104. To determine if marker alleles could be used to differentiate Usher type IIa from Usher IIb, parental chromosomes of the 26 Usher II a families were analysed for significant non-random association of spe cific alleles from flanking loci with USH2a, but no linkage disequilib rium was observed in this Dutch population.