Abstract
We show that massively parallel targeted sequencing of 19 genes provides a new and reliable strategy for molecular diagnosis of Usher syndrome (USH) and nonsyndromic deafness, particularly appropriate for these disorders characterized by a high clinical and genetic heterogeneity and a complex structure of several of the genes involved. A series of 71 patients including Usher patients previously screened by Sanger sequencing plus newly referred patients was studied. Ninety-eight percent of the variants previously identified by Sanger sequencing were found by next-generation sequencing (NGS). NGS proved to be efficient as it offers analysis of all relevant genes which is laborious to reach with Sanger sequencing. Among the 13 newly referred Usher patients, both mutations in the same gene were identified in 77% of cases (10 patients) and one candidate pathogenic variant in two additional patients. This work can be considered as pilot for implementing NGS for genetically heterogeneous diseases in clinical service.
Highlights
Usher syndrome (USH) is an autosomal recessive disorder with a prevalence of at least 5/100,000 characterized by the association of sensorineural hearing loss (HL) and visual impairment due to retinitis pigmentosa (RP)
This includes screening for large rearrangements (Le Guedard et al 2007; Roux et al 2011) and the analysis of USH transcripts from nasal epithelial cells (Vache et al 2010, 2012) as well as the development of a multistep analysis to interpret the variants of unknown clinical significance (Baux et al 2013)
Because Sanger sequencing is time consuming, we included a preliminary linkage analysis at the USH1 loci that prioritizes the gene to be sequenced in 44% of the cases
Summary
Usher syndrome (USH) is an autosomal recessive disorder with a prevalence of at least 5/100,000 characterized by the association of sensorineural hearing loss (HL) and visual impairment due to retinitis pigmentosa (RP). USH is the most common form of deaf–blindness (Saihan et al.2009). Three clinical subtypes (USH1, USH2, and USH3) are distinguished depending on the severity and progression of HL and presence or absence of vestibular areflexia and this distinction is generally used to guide molecular diagnosis. USH1 is the most severe form with congenital profound HL and vestibular areflexia. USH2 is the most common clinical form of the disorder, accounting for a 2013 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc
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