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Background  Usher Syndrome is the leading cause of inherited deaf-blindness. It is divided into three subtypes, of which the most common is Usher type 2, and the  USH2A  gene accounts for 75-80% of cases. Despite recent sequencing strategies, in our cohort a significant proportion of individuals with Usher type 2 have just one heterozygous disease-causing mutation in  USH2A , or no convincing disease-causing mutations across nine Usher genes. The purpose of this study was to improve the molecular diagnosis in these families by screening  USH2A  for duplications, heterozygous deletions and a common pathogenic deep intronic variant  USH2A : c.7595-2144A>G.    Methods  Forty-nine Usher type 2 or atypical Usher families who had missing mutations (mono-allelic  USH2A  or no mutations following Sanger sequencing of nine Usher genes) were screened for duplications/deletions using the  USH2A  SALSA MLPA reagent kit (MRC-Holland). Identification of  USH2A : c.7595-2144A>G was achieved by Sanger sequencing. Mutations were confirmed by a combination of reverse transcription PCR using RNA extracted from nasal epithelial cells or fibroblasts, and by array comparative genomic hybridisation with sequencing across the genomic breakpoints.    Results  Eight mutations were identified in 23 Usher type 2 families (35%) with one previously identified heterozygous disease-causing mutation in  USH2A . These consisted of five heterozygous deletions, one duplication, and two heterozygous instances of the pathogenic variant  USH2A : c.7595-2144A>G. No variants were found in the 15 Usher type 2 families with no previously identified disease-causing mutations. In 11 atypical families, none of whom had any previously identified convincing disease-causing mutations, the mutation  USH2A : c.7595-2144A>G was identified in a heterozygous state in one family. All five deletions and the heterozygous duplication we report here are novel. This is the first time that a duplication in  USH2A  has been reported as a cause of Usher syndrome.    Conclusions  We found that 8 of 23 (35%) of ‘missing’ mutations in Usher type 2 probands with only a single heterozygous  USH2A  mutation detected with Sanger sequencing could be attributed to deletions, duplications or a pathogenic deep intronic variant. Future mutation detection strategies and genetic counselling will need to take into account the prevalence of these types of mutations in order to provide a more comprehensive diagnostic service.

orphanet journal of rare diseases

Screening for duplications, deletions and a common intronic mutation detects 35% of second mutations in patients with USH2A monoallelic mutations on Sanger sequencing