Open AccessNext‐generation sequencing reveals the mutational landscape of clinically diagnosed Usher syndrome: copy number variations, phenocopies, a predominant target for translational read‐through, and PEX 26 mutated in Heimler syndrome
Author(s) -
Neuhaus Christine,
Eisenberger Tobias,
Decker Christian,
Nagl Sandra,
Blank Cornelia,
Pfister Markus,
Kennerknecht Ingo,
MüllerHofstede Cornelie,
Charbel Issa Peter,
Heller Raoul,
Beck Bodo,
Rüther Klaus,
Mitter Diana,
Rohrschneider Klaus,
Steinhauer Ute,
Korbmacher Heike M.,
Huhle Dagmar,
Elsayed Solaf M.,
Taha Hesham M.,
Baig Shahid M.,
Stöhr Heidi,
Preising Markus,
Markus Susanne,
Moeller Fabian,
Lorenz Birgit,
NagelWolfrum Kerstin,
Khan Arif O.,
Bolz Hanno J.
Publication year - 2017
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.312
Subject(s) - usher syndrome , retinitis pigmentosa , genetics , sanger sequencing , biology , copy number variation , multiplex ligation dependent probe amplification , phenocopy , point mutation , mutation , bioinformatics , gene , medicine , phenotype , exon , genome
Background Combined retinal degeneration and sensorineural hearing impairment is mostly due to autosomal recessive Usher syndrome ( USH 1: congenital deafness, early retinitis pigmentosa ( RP ); USH 2: 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 USH 1 and USH 2 patients, with biallelic mutations in 97% ( USH 1) and 90% ( USH 2), respectively. Quantitative readout reliably detected CNV s (confirmed by MLPA or array‐ CGH ), qualifying targeted NGS as one tool for detecting point mutations and CNV s. CNV s accounted for 10% of identified USH 2A alleles, often in trans to seemingly monoallelic point mutations. We demonstrate PTC 124‐induced read‐through of the common p.Trp3955* nonsense mutation (13% of detected USH 2A 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 NR 2E3 , genes implicated in isolated deafness and RP . Two patients with additional enamel dysplasia had biallelic PEX 26 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.