Partial USH2A deletions contribute to Usher syndrome in Denmark

Abstract

Usher syndrome is an autosomal recessive disorder characterized by congenital hearing impairment, progressive visual loss owing to retinitis pigmentosa and in some cases vestibular dysfunction. Usher syndrome is divided into three subtypes, USH1, USH2 and USH3. Twelve loci and eleven genes have so far been identified. Duplications and deletions in PCDH15 and USH2A that lead to USH1 and USH2, respectively, have previously been identified in patients from United Kingdom, Spain and Italy. In this study, we investigate the proportion of exon deletions and duplications in PCDH15 and USH2A in 20 USH1 and 30 USH2 patients from Denmark using multiplex ligation-dependent probe amplification (MLPA). Two heterozygous deletions were identified in USH2A, but no deletions or duplications were identified in PCDH15. Next-generation mate-pair sequencing was used to identify the exact breakpoints of the two deletions identified in USH2A. Our results suggest that USH2 is caused by USH2A exon deletions in a small fraction of the patients, whereas deletions or duplications in PCDH15 might be rare in Danish Usher patients.

The role of CNVs in the etiology of rare autosomal recessive disorders: the example of TRAPPC9-associated intellectual disability

“…Deletion of an allele, intragenic deletion, and intragenic duplication behave as loss-of-function variants. In genetically heterogeneous conditions, such as Usher syndrome [11], Cohen syndrome, genetics deafness, retinal dystrophies, and ciliopathies [12], diagnosis strategies include aCGH in addition to gene sequencing in order to detect genomic rearrangements. The proportion of large genomic rearrangements could reach up to one-third of all mutational events [13].…”

Usher syndrome in Denmark: mutation spectrum and some clinical observations

“…To obtain an overall picture of molecular findings in patients with USH registered at the Danish National Eye Clinic for the Visually Impaired, we pooled the mutation data obtained from cohort 1 (21 unrelated cases) with all previously published mutation data from Danish USH patients (79 unrelated cases; Janecke et al 1999;Dreyer et al 2000Dreyer et al , 2008Cremers et al 2007;Tranebjaerg et al 2011;Dad et al 2015). In total, we collected mutation data from 100 USH probands.…”

“…A: targeted NGS of USH genes, B: APEX microarray (Dreyer et al 2008). C: USH1C Sanger sequencing (Dad et al 2015). D: USH2A Sanger sequencing (Janecke et al 1999;Dreyer et al 2000).…”

“…Recently USH patients were investigated for exon deletions/duplications in USH2A and PCDH15 by Multiplex ligation‐dependent probe amplification (MLPA); Dad et al. .…”

“…Mixed groups of USH cases have been investigated for mutations in several genes using Arrayed Primer EXtension (APEX); Cremers et al 2007;Tranebjaerg et al 2011. Recently USH patients were investigated for exon deletions/ duplications in USH2A and PCDH15 by Multiplex ligationdependent probe amplification (MLPA); Dad et al 2015. This study presents the results of molecular examinations of 26 individuals with USH residing in Denmark using a combination of APEX microarray for identification of previously reported mutations, traditional Sanger sequencing of single candidate genes, or targeted Next-Generation Sequencing (NGS) of a panel of 10 genes, associated with USH.…”