Genetic causes of deaf‐blindness in sixteen Czech families

Purpose Usher syndrome (USH) is the most common cause of hereditary deaf‐blindness in humans with an estimated prevalence of 3‐6 per 100,000 inhabitants. USH is inherited as an autosomal recessive trait and is clinically divided into three types based on audiological profile and vestibular symptoms. The aim of the project was to phenotype the first cohort of Czech patients with USH (16 families, 21 affected individuals) and to perform investigation into the molecular genetic cause of their disease. Methods Sanger sequencing of 6 frequently mutated USH2A exons was performed as an initial step in probands suspected to suffer from USH type II. Unsolved cases were then investigated by a range of techniques including whole‐exome sequencing, targeted gene panel next generation sequencing and single‐nucleotide polymorphism (SNP) array for copy number variation analysis. Detected missense mutations were evaluated for pathogenicity by six in silico tools. Mutations were verified and their segregation within the families was performed by Sanger sequencing. Results In total 17 different mutations evaluated as pathogenic were identified in 20 individuals (95%) from 15 families, of these c.1256G>A, c.13342_13347del, deletion of exons 33 and 34 in USH2A, c.871G>A in CDH23 and c.937C>T in USH1C were novel. A known c.11864G>A in USH2A was the most prevalent mutation observed, found either in a homozygous or compound heterozygous state in 9 families. SNP haplotype analysis supported the hypothesis of a founder effect. Investigation into the geographic origin suggested regional clustering of the c.11864G>A allele in Southeastern part of the Czech Republic. Conclusions The proposed research will help to elucidate factors involved in the etiopathogenesis of USH, which is important for prognosis, patient counseling, management, development and introduction of novel therapies.