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.

• Keywords
• DFNB1 region, GJB2 monoallelic variant, hearing loss, next generation sequencing,
• MeSH
• Gene Frequency MeSH
• Heterozygote MeSH
• Connexin 26 genetics   MeSH
• Humans MeSH
• Mutation MeSH
• Hearing Loss, Sensorineural genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• GJB2 protein, human MeSH Browser
• Connexin 26 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.

• Keywords
• Audiological phenotype, Autosomal recessive nonsyndromic hearing loss, DFNB16, Genotype/phenotype correlation, STRC, Stereocilin,
• MeSH
• Alleles MeSH
• Audiometry MeSH
• Child MeSH
• Adult MeSH
• Genetic Association Studies MeSH
• Deafness genetics   MeSH
• Polymorphism, Single Nucleotide genetics   MeSH
• Connexins genetics   MeSH
• Humans MeSH
• Membrane Proteins genetics   MeSH
• Intercellular Signaling Peptides and Proteins genetics   MeSH
• Adolescent MeSH
• Young Adult MeSH
• Mutation genetics   MeSH
• Hearing Loss, Sensorineural diagnosis   genetics   MeSH
• Polymerase Chain Reaction MeSH
• Sequence Deletion genetics   MeSH
• Hearing Tests MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Connexins MeSH
• Membrane Proteins MeSH
• Intercellular Signaling Peptides and Proteins MeSH
• STRC protein, human MeSH Browser

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.

• Keywords
• genetics, hearing loss, nonsyndromic, sensorineural,
• MeSH
• Actins genetics   MeSH
• Child MeSH
• Adult MeSH
• KCNQ Potassium Channels genetics   MeSH
• Extracellular Matrix Proteins genetics   MeSH
• Deafness genetics   MeSH
• Infant MeSH
• Connexin 26 MeSH
• Connexins genetics   MeSH
• Middle Aged MeSH
• Humans MeSH
• Membrane Proteins genetics   MeSH
• Microfilament Proteins genetics   MeSH
• Adolescent MeSH
• Young Adult MeSH
• Mutation genetics   MeSH
• DNA Mutational Analysis methods   MeSH
• Hearing Loss, Sensorineural genetics   MeSH
• Child, Preschool MeSH
• Serpins genetics   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Infant MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Czech Republic MeSH
• Names of Substances
• ACTG1 protein, human MeSH Browser
• Actins MeSH
• COCH protein, human MeSH Browser
• KCNQ Potassium Channels MeSH
• ESPN protein, human MeSH Browser
• Extracellular Matrix Proteins MeSH
• GJB2 protein, human MeSH Browser
• GJB3 protein, human MeSH Browser
• KCNQ4 protein, human MeSH Browser
• Connexin 26 MeSH
• Connexins MeSH
• Membrane Proteins MeSH
• Microfilament Proteins MeSH
• serpin B6 MeSH Browser
• Serpins MeSH
• TMIE protein, human MeSH Browser

BACKGROUND: In the present study we aimed: 1) To establish the prevalence and clinical impact of DFNB49 mutations in deaf Roma from 2 Central European countries (Slovakia and Hungary), and 2) to analyze a possible common origin of the c.1331+2T>C mutation among Roma and Pakistani mutation carriers identified in the present and previous studies. METHODS: We sequenced 6 exons of the MARVELD2 gene in a group of 143 unrelated hearing impaired Slovak Roma patients. Simultaneously, we used RFLP to detect the c.1331+2T>C mutation in 85 Hungarian deaf Roma patients, control groups of 702 normal hearing Romanies from both countries and 375 hearing impaired Slovak Caucasians. We analyzed the haplotype using 21 SNPs spanning a 5.34Mb around the mutation c.1331+2T>C. RESULTS: One pathogenic mutation (c.1331+2T>C) was identified in 12 homozygous hearing impaired Roma patients. Allele frequency of this mutation was higher in Hungarian (10%) than in Slovak (3.85%) Roma patients. The identified common haplotype in Roma patients was defined by 18 SNP markers (3.89 Mb). Fourteen common SNPs were also shared among Pakistani and Roma homozygotes. Biallelic mutation carriers suffered from prelingual bilateral moderate to profound sensorineural hearing loss. CONCLUSIONS: We demonstrate different frequencies of the c.1331+2T>C mutation in hearing impaired Romanies from 3 Central European countries. In addition, our results provide support for the hypothesis of a possible common ancestor of the Slovak, Hungarian and Czech Roma as well as Pakistani deaf patients. Testing for the c.1331+2T>C mutation may be recommended in GJB2 negative Roma cases with early-onset sensorineural hearing loss.

• MeSH
• Alleles MeSH
• Founder Effect MeSH
• Exons genetics   MeSH
• Gene Frequency MeSH
• Genotype MeSH
• Haplotypes genetics   MeSH
• Polymorphism, Single Nucleotide * MeSH
• Infant MeSH
• Connexin 26 MeSH
• Connexins MeSH
• Humans MeSH
• MARVEL Domain Containing 2 Protein genetics   MeSH
• Mutation * MeSH
• Hearing Loss congenital   ethnology   genetics   MeSH
• Prevalence MeSH
• Roma genetics   MeSH
• Sequence Homology, Nucleic Acid MeSH
• Age of Onset MeSH
• Check Tag
• Infant MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Comparative Study MeSH
• Geographicals
• Czech Republic ethnology   MeSH
• Hungary ethnology   MeSH
• Pakistan ethnology   MeSH
• Slovakia ethnology   MeSH
• Names of Substances
• GJB2 protein, human MeSH Browser
• Connexin 26 MeSH
• Connexins MeSH
• MARVELD2 protein, human MeSH Browser
• MARVEL Domain Containing 2 Protein MeSH

Pendred syndrome is an autosomal recessive disorder characterised by sensorineural hearing loss and thyroid dyshormonogenesis. It is caused by mutations in the PDS/SLC26A4 gene (OMIM 605646) encoding for pendrin. Hypothyroidism in Pendred syndrome can be--although rarely--present from birth and therefore diagnosed by neonatal screening. The aim of our study was to identify patients with Pendred syndrome among a historical cohort of patients with congenital hypothyroidism (CH) identified by neonatal screening, and to find their mutations in the PDS/SLC26A4 gene. We investigated 197 Czech Caucasian children with CH detected by the neonatal screening between the years 1985 and 2005. The clinical diagnosis of Pendred syndrome was based on the laboratory and sonographic signs of thyroid dyshormonogenesis in association with sensorineural hearing loss. In subjects clinically diagnosed with Pendred syndrome, we sequenced all exons and exon-intron boundaries of the PDS/SLC26A4 gene. Hearing loss was present in 10/197 children with screening-detected CH. Of these, three fulfilled the diagnostic criteria of Pendred syndrome. Two patients were compound heterozygotes for PDS/SLC26A4 mutations: patient 1 carried c.2089+1G>A / c.3G>C and patient 2 carried p.Tyr530His / p.Val422Asp. Two of the four identified mutations were novel (c.3G>C in patient 1 and p.Val422Asp in patient 2). The third patient was free of mutations in the PDS/SLC26A4 gene, representing a phenocopy. In conclusion, our results indicate the rarity of Pendred syndrome as a cause of CH. The identification of two novel mutations expands the spectrum of mutations in the PDS/SLC26A4 gene and emphasizes their marked allelic heterogeneity.

• MeSH
• Child MeSH
• Anion Exchange Protein 1, Erythrocyte genetics   MeSH
• Congenital Hypothyroidism complications   diagnosis   genetics   MeSH
• Humans MeSH
• Adolescent MeSH
• Mutation MeSH
• Infant, Newborn MeSH
• Neonatal Screening methods   MeSH
• Hearing Loss, Sensorineural complications   diagnosis   genetics   MeSH
• Pedigree MeSH
• Syndrome MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Infant, Newborn MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Anion Exchange Protein 1, Erythrocyte MeSH
• SLC4A1 protein, human MeSH Browser