Hearing loss is a genetically heterogeneous sensory defect, and the frequent causes are biallelic pathogenic variants in the GJB2 gene. However, patients carrying only one heterozygous pathogenic (monoallelic) GJB2 variant represent a long-lasting diagnostic problem. Interestingly, previous results showed that individuals with a heterozygous pathogenic GJB2 variant are two times more prevalent among those with hearing loss compared to normal-hearing individuals. This excess among patients led us to hypothesize that there could be another pathogenic variant in the GJB2 region/DFNB1 locus. A hitherto undiscovered variant could, in part, explain the cause of hearing loss in patients and would mean reclassifying them as patients with GJB2 biallelic pathogenic variants. In order to detect an unknown causal variant, we examined 28 patients using NGS with probes that continuously cover the 0.4 Mb in the DFNB1 region. An additional 49 patients were examined by WES to uncover only carriers. We did not reveal a second pathogenic variant in the DFNB1 region. However, in 19% of the WES-examined patients, the cause of hearing loss was found to be in genes other than the GJB2. We present evidence to show that a substantial number of patients are carriers of the GJB2 pathogenic variant, albeit only by chance.

• Klíčová slova
• DFNB1 region, GJB2 monoallelic variant, hearing loss, next generation sequencing,
• MeSH
• frekvence genu MeSH
• heterozygot MeSH
• konexin 26 genetika   MeSH
• lidé MeSH
• mutace MeSH
• percepční nedoslýchavost genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• GJB2 protein, human MeSH Prohlížeč
• konexin 26 MeSH

BACKGROUND AND OBJECTIVE: Hearing loss is the most common sensory deficit in humans. The aim of this study was to clarify the genetic aetiology of nonsyndromic hearing loss in the Moravian-Silesian population of the Czech Republic. PATIENTS AND METHODS: This study included 200 patients (93 males, 107 females, mean age 16.9 years, ranging from 4 months to 62 years) with nonsyndromic sensorineural hearing loss. We screened all patients for mutations in GJB2 and the large deletion del(GJB6-D13S1830). We performed further screening for additional genes (SERPINB6, TMIE, COCH, ESPN, ACTG1, KCNQ4, and GJB3) with Sanger sequencing on a subset of patients that were negative for GJB2 mutations. RESULTS: We detected biallelic GJB2 mutations in 44 patients (22%). Among these patients, 63.6%, 9.1% and 2.3% exhibited homozygous c.35delG, p.Trp24*, and p.Met34Thr mutations, respectively. The remaining 25% of these patients exhibited compound heterozygous c.35delG, c.-23+1G>A, p.Trp24*, p.Val37Ile, p.Met34Thr, p.Leu90Pro, c.235delC, c.313_326del14, p.Ser139Asn, and p.Gly147Leu mutations. We found a monoallelic GJB2 mutation in 12 patients (6.6%). We found no pathogenic mutations in the other tested genes. Conclusions: One fifth of our cohort had deafness related to GJB2 mutations. The del(GJB6-D13S1830), SERPINB6, TMIE, COCH, ESPN, ACTG1, GJB3, and KCNQ4 mutations were infrequently associated with deafness in the Moravian-Silesian population. Therefore, we suggest that del(GJB6-D13S1830) testing should be performed only when patients with deafness carry the monoallelic GJB2 mutation.

• Klíčová slova
• genetics, hearing loss, nonsyndromic, sensorineural,
• MeSH
• aktiny genetika   MeSH
• dítě MeSH
• dospělí MeSH
• draslíkové kanály KCNQ genetika   MeSH
• extracelulární matrix - proteiny genetika   MeSH
• hluchota genetika   MeSH
• kojenec MeSH
• konexin 26 MeSH
• konexiny genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• membránové proteiny genetika   MeSH
• mikrofilamentové proteiny genetika   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mutace genetika   MeSH
• mutační analýza DNA metody   MeSH
• percepční nedoslýchavost genetika   MeSH
• předškolní dítě MeSH
• serpiny genetika   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• ACTG1 protein, human MeSH Prohlížeč
• aktiny MeSH
• COCH protein, human MeSH Prohlížeč
• draslíkové kanály KCNQ MeSH
• ESPN protein, human MeSH Prohlížeč
• extracelulární matrix - proteiny MeSH
• GJB2 protein, human MeSH Prohlížeč
• GJB3 protein, human MeSH Prohlížeč
• KCNQ4 protein, human MeSH Prohlížeč
• konexin 26 MeSH
• konexiny MeSH
• membránové proteiny MeSH
• mikrofilamentové proteiny MeSH
• serpin B6 MeSH Prohlížeč
• serpiny MeSH
• TMIE protein, human MeSH Prohlížeč