Genetics of Usher disease. USH

Usher Syndrome (USH) is a genetically and clinically heterogeneous combination of retinitis pigmentosa, hearing loss and vestibular dysfunction. The aim of this study was to characterize the set of genes and mutations that cause USH in the Israeli and Palestinian populations. Eighty-five families with USH were recruited [27 with USH type 1 (USH1), 38 with USH2, 8 with USH3, one with atypical USH, and 11 families with an undetermined USH type]. All affected subjects underwent a full ocular evaluation. A comprehensive genetic analysis, including Sanger sequencing for the detection of founder mutations, homozygosity mapping (HM) in some consanguineous families, and whole exome sequencing (WES) in large families was performed. In 67% of the families (57 out of 85) an autosomal recessive inheritance could be determined. A mutation detection analysis (including HM, founder mutations and WES) led to the identification of causative mutations in 45 (53%) of the families including 19 families with mutations in USH2A, 16 in MYO7A, 7 in USH3A, 1 in GPR98, 1 in PCDH15 and 1 in CEP250. Our analysis revealed 25 mutations, 10 of which are novel (including p.Tyr1768* in CLRN1, p.G1298R and c.2187+1G>T in MYO7A and p.K5l65fs in GPR98). To the best of our knowledge, this is the largest report of a genetic analysis of Israeli and Palestinian families (n=85) with different USH subtypes.