New Search

Export article
Open Access

Next-generation sequencing reveals the mutational landscape of clinically diagnosed Usher syndrome: copy number variations, phenocopies, a predominant target for translational read-through, andPEX26mutated in Heimler syndrome

Christine Neuhaus, Tobias Eisenberger, Christian Decker, Sandra Nagl, Cornelia Blank, Markus Pfister, Ingo Kennerknecht, Cornelie Müller-Hofstede, Peter Charbel Issa , Raoul Heller, Bodo Beck, Klaus Rüther, Diana Mitter, Klaus Rohrschneider, Ute Steinhauer, Heike M. Korbmacher, Dagmar Huhle, Solaf M. Elsayed, Hesham M. Taha, Shahid M. Baig, Heidi Stöhr, Markus Preising, Preising Markus, Fabian Moeller, Birgit Lorenz, Kerstin Nagel-Wolfrum, Arif O. Khan, Hanno J. Bolz
Published: 6 July 2017
 by  Wiley
Molecular Genetics & Genomic Medicine , Volume 5, pp 531-552; doi:10.1002/mgg3.312

Abstract: Combined retinal degeneration and sensorineural hearing impairment is mostly due to autosomal recessive Usher syndrome (USH1: congenital deafness, early retinitis pigmentosa (RP); USH2: progressive hearing impairment, RP). Sanger sequencing and NGS of 112 genes (Usher syndrome, nonsyndromic deafness, overlapping conditions), MLPA, and array-CGH were conducted in 138 patients clinically diagnosed with Usher syndrome. A molecular diagnosis was achieved in 97% of both USH1 and USH2 patients, with biallelic mutations in 97% (USH1) and 90% (USH2), respectively. Quantitative readout reliably detected CNVs (confirmed by MLPA or array-CGH), qualifying targeted NGS as one tool for detecting point mutations and CNVs. CNVs accounted for 10% of identified USH2A alleles, often in trans to seemingly monoallelic point mutations. We demonstrate PTC124-induced read-through of the common p.Trp3955* nonsense mutation (13% of detected USH2A alleles), a potential therapy target. Usher gene mutations were found in most patients with atypical Usher syndrome, but the diagnosis was adjusted in case of double homozygosity for mutations in OTOA and NR2E3, genes implicated in isolated deafness and RP. Two patients with additional enamel dysplasia had biallelic PEX26 mutations, for the first time linking this gene to Heimler syndrome. Targeted NGS not restricted to Usher genes proved beneficial in uncovering conditions mimicking Usher syndrome.
Keywords: copy number variation / Heimler Syndrome / phenocopies / Usher syndrome / Next‐generation sequencing / translational read‐through

Scifeed alert for new publications

Never miss any articles matching your research from any publisher
  • Get alerts for new papers matching your research
  • Find out the new papers from selected authors
  • Updated daily for 49'000+ journals and 6000+ publishers
  • Define your Scifeed now

Share this article

Click here to see the statistics on "Molecular Genetics & Genomic Medicine" .
References (119)
    Cited by 22 articles
      Back to Top Top