Journal article
Authors list: Neuhaus, Christine; Eisenberger, Tobias; Decker, Christian; Nagl, Sandra; Blank, Cornelia; Pfister, Markus; Kennerknecht, Ingo; Mueller-Hofstede, Cornelie; Issa, Peter Charbel; Heller, Raoul; Beck, Bodo; Ruether, Klaus; Mitter, Diana; Rohrschneider, Klaus; Steinhauer, Ute; Korbmacher, Heike M.; Huhle, Dagmar; Elsayed, Solaf M.; Taha, Hesham M.; Baig, Shahid M.; Stoehr, Heidi; Preising, Markus; Markus, Susanne; Moeller, Fabian; Lorenz, Birgit; Nagel-Wolfrum, Kerstin; Khan, Arif O.; Bolz, Hanno J.
Publication year: 2017
Pages: 531-552
Journal: Molecular Genetics and Genomic Medicine
Volume number: 5
Issue number: 5
ISSN: 2324-9269
Open access status: Gold
DOI Link: https://doi.org/10.1002/mgg3.312
Publisher: Wiley
BackgroundCombined 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). MethodsSanger 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. ResultsA 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. ConclusionTargeted NGS not restricted to Usher genes proved beneficial in uncovering conditions mimicking Usher syndrome.
Abstract:
Citation Styles
Harvard Citation style: Neuhaus, C., Eisenberger, T., Decker, C., Nagl, S., Blank, C., Pfister, M., et al. (2017) 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, Molecular Genetics and Genomic Medicine, 5(5), pp. 531-552. https://doi.org/10.1002/mgg3.312
APA Citation style: Neuhaus, C., Eisenberger, T., Decker, C., Nagl, S., Blank, C., Pfister, M., Kennerknecht, I., Mueller-Hofstede, C., Issa, P., Heller, R., Beck, B., Ruether, K., Mitter, D., Rohrschneider, K., Steinhauer, U., Korbmacher, H., Huhle, D., Elsayed, S., Taha, H., ...Bolz, H. (2017). 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. Molecular Genetics and Genomic Medicine. 5(5), 531-552. https://doi.org/10.1002/mgg3.312
Keywords
CONTIGUOUS GENE; HEARING-LOSS; Heimler syndrome; INFANTILE HYPERINSULINISM; MOLECULAR DIAGNOSIS; MYOSIN VIIA GENE; PEROXISOME-BIOGENESIS DISORDERS; phenocopies; RETINITIS-PIGMENTOSA; S-CONE-SYNDROME; SYNDROME TYPE IIA; translational read-through; USH2A GENE; Usher syndrome
