Next‐generation sequencing reveals the mutational landscape of clinically diagnosed Usher syndrome: copy number variations, phenocopies, a predominant target for translational read‐through, and PEX26 mutated in Heimler syndrome
| Autor: | Arif O. Khan, Susanne Markus, Raoul Heller, Solaf M. Elsayed, Ute Steinhauer, Heike M. Korbmacher, Kerstin Nagel-Wolfrum, Markus Pfister, Diana Mitter, Christian Decker, Birgit Lorenz, Markus N. Preising, Ingo Kennerknecht, Shahid Mahmood Baig, Heidi Stöhr, Cornelie Müller-Hofstede, Klaus Rohrschneider, Fabian Moeller, Peter Charbel Issa, Tobias Eisenberger, Christine Neuhaus, Hanno J. Bolz, Klaus Rüther, Sandra Nagl, Bodo B. Beck, Cornelia Blank, Dagmar Huhle, Hesham Taha |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Usher syndrome Nonsense mutation next‐generation sequencing Biology Gene mutation Bioinformatics 03 medical and health sciences symbols.namesake Retinitis pigmentosa Genetics medicine otorhinolaryngologic diseases Multiplex ligation-dependent probe amplification Nonsyndromic deafness Molecular Biology Genetics (clinical) Sanger sequencing Heimler syndrome Copy number variation Point mutation Original Articles medicine.disease eye diseases 030104 developmental biology symbols phenocopies translational read‐through Original Article |
| Zdroj: | Molecular Genetics & Genomic Medicine |
| ISSN: | 2324-9269 |
| Popis: | Background 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). Methods 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. Results 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. Conclusion Targeted NGS not restricted to Usher genes proved beneficial in uncovering conditions mimicking Usher syndrome. |
| Databáze: | OpenAIRE |
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