Marková, Simona Poisson*
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Non-syndromic autosomal recessive hearing loss is an extremely heterogeneous disease caused by mutations in more than 80 genes. We examined Czech patients with early/prelingual non-syndromic, presumably genetic hearing loss (NSHL) without known cause after GJB2 gene testing. Four hundred and twenty-one unrelated patients were examined for STRC gene deletions with quantitative comparative fluorescent PCR (QCF PCR), 197 unrelated patients with next-generation sequencing by custom-designed NSHL gene panels and 19 patients with whole-exome sequencing (WES). Combining all methods, we discovered the cause of the disease in 54 patients. The most frequent type of NSHL was DFNB16 (STRC), which was detected in 22 patients, almost half of the clarified patients. Other biallelic pathogenic mutations were detected in the genes: MYO15A, LOXHD1, TMPRSS3 (each gene was responsible for five clarified patients, CDH23 (four clarified patients), OTOG and OTOF (each gene was responsible for two clarified patients). Other genes (AIFM1, CABP2, DIAPH1, PTPRQ, RDX, SLC26A4, TBC1D24, TECTA, TMC1) that explained the cause of hearing impairment were further detected in only one patient for each gene. STRC gene mutations, mainly deletions remain the most frequent NSHL cause after mutations in the GJB2.
- MeSH
- dítě MeSH
- dospělí MeSH
- genetická predispozice k nemoci MeSH
- hluchota embryologie genetika patologie MeSH
- kadheriny genetika MeSH
- konexin 26 genetika MeSH
- lidé MeSH
- membránové glykoproteiny genetika MeSH
- membránové proteiny genetika MeSH
- mezibuněčné signální peptidy a proteiny genetika MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mutace genetika MeSH
- myosiny genetika MeSH
- nádorové proteiny genetika MeSH
- nedoslýchavost epidemiologie genetika patologie MeSH
- sekvenování exomu MeSH
- serinové endopeptidasy genetika MeSH
- transportní proteiny genetika MeSH
- vysoce účinné nukleotidové sekvenování MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
INTRODUCTION: Hearing loss (HL) is the most common sensory deficit in humans. HL is an extremely heterogeneous condition presenting most frequently as a nonsyndromic (NS) condition inherited in an autosomal recessive (AR) pattern, termed DFNB. Mutations affecting the STRC gene cause DFNB type 16. Various types of mutations within the STRC gene have been reported from the U.S. and German populations, but no information about the relative contribution of STRC mutations to NSHL-AR among Czech patients is available. METHODS AND PATIENTS: Two hundred and eighty-eight patients with prelingual NSHL, either sporadic (n = 207) or AR (n = 81), who had been previously tested negative for the mutations affecting the GJB2 gene, were included in the study. These patients were tested for STRC mutations by a quantitative comparative fluorescent polymerase chain reaction (QF-PCR) assay. In addition, 31 of the 81 NSHL-AR patients were analyzed by massively parallel sequencing using one of two different gene panels: 23 patients were analyzed by multiplex-ligation probe amplification (MLPA); and 9 patients by SNP microarrays. RESULTS: Causal mutations affecting the STRC gene (including copy number variations [CNVs] and point mutations) were found in 5.5% of all patients and 13.6% of the 81 patients in the subgroup with NSHL-AR. CONCLUSION: Our results provide strong evidence that STRC gene mutations are an important cause of NSHL-AR in Czech HL patients and are probably the second most common cause of DFNB. Large CNVs were more frequent than point mutations and it is reasonable to test them first by a QF-PCR method-a simple, accessible, and efficient tool for STRC CNV detection, which can be combined by MLPA.
- MeSH
- lidé MeSH
- membránové proteiny genetika MeSH
- mutace * MeSH
- nedoslýchavost genetika MeSH
- polymerázová řetězová reakce MeSH
- sekvenční delece MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
INTRODUCTION: Hearing loss is the most frequent sensory disorder and is genetically extremely heterogeneous. By far the most frequent cause of nonsyndromic autosomal recessive hearing loss (AR-NSHL) are biallelic pathogenic mutations in the GJB2 gene causing DFNB1. The worldwide search for the second most common type of AR-NSHL took almost two decades. Recently reported alterations (mostly deletions) of the STRC gene, also named DFNB16, seem to be the second most frequent cause of AR-NSHL. Genetic testing of STRC is very challenging due to the highly homologous pseudogene. Anecdotal evidence from single patients shows that STRC mutations have their typical audiological findings and patients usually have moderate hearing loss. The aim of this study is to discover if audiological findings in patients with biallelic pathogenic mutations affecting STRC have the characteristic features and shape of audiological curves and if there are genotype/phenotype correlations in relation to various types of STRC mutations. METHODS: Eleven hearing loss patients with pathogenic mutations on both alleles of the STRC gene were detected during routine genetic examination of AR-NSHL patients. Audiological examination consisted of pure tone audiometry, stapedial reflexes, tympanometry and otoacoustic emission tests. RESULTS: The threshold of pure tone average (PTA) was 46 dB and otoacoustic emissions were not detectable in these DFNB16 patients. All patients were without vestibular irritation or asymmetry. CONCLUSION: Moderate sensorineural hearing loss is typical for DFNB16-associated hearing loss and there are no significant differences in audiological phenotypes among different types of mutations affecting STRC.
- MeSH
- alely MeSH
- audiometrie MeSH
- dítě MeSH
- dospělí MeSH
- genetické asociační studie MeSH
- hluchota genetika MeSH
- jednonukleotidový polymorfismus genetika MeSH
- konexiny genetika MeSH
- lidé MeSH
- membránové proteiny genetika MeSH
- mezibuněčné signální peptidy a proteiny genetika MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mutace genetika MeSH
- percepční nedoslýchavost diagnóza genetika MeSH
- polymerázová řetězová reakce MeSH
- sekvenční delece genetika MeSH
- sluchové testy MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH