RESUMO
Confirmation of the newly described 1p36.13-1p36.12 microdeletion syndrome by finding of a 2,2 Mb deletion in the critical region in a Czech two generation family with a very similar phenotype, but in addition also polyneuropathy of lower limbs.
Assuntos
Deleção Cromossômica , Transtornos Cromossômicos , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 1/genética , República Tcheca , Humanos , Fenótipo , SíndromeRESUMO
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.
Assuntos
Conexina 26/genética , Surdez/genética , Perda Auditiva/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Adolescente , Adulto , Proteínas Relacionadas a Caderinas , Caderinas/genética , Proteínas de Transporte/genética , Criança , República Tcheca/epidemiologia , Surdez/embriologia , Surdez/patologia , Feminino , Predisposição Genética para Doença , Perda Auditiva/epidemiologia , Perda Auditiva/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Glicoproteínas de Membrana/genética , Proteínas de Membrana/genética , Mutação/genética , Miosinas/genética , Proteínas de Neoplasias/genética , Serina Endopeptidases/genética , Sequenciamento do Exoma , Adulto JovemRESUMO
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.