According to ACMG guidelines, most of these mutations were classified as likely pathogenic, although there are three variations of uncertain significance, we suggest that they are important to study the etiology of the family, thus we have included them in the table ( Table 1, Supplementary Figure).
Among them, there are 9 novel mutations that have not been reported previously in this study. The co-segregation of the reported mutations was confirmed with the hearing phenotype in these family members by Sanger sequencing ( Supplementary Table 2). While in the four dominant families, we identified four dominant deafness-related heterozygous variants, c.61_62insGGACCCGCAGTTGCAGC in TIMM8A (OMIM 300356) for Family F, c.733delA in MITF (OMIM 156845) for Family G, p.H313Y in WFS1 (OMIM 606201) for Family H, and p.A677T in WFS1 (OMIM 606201) for Family I, co-segregating with the hearing impairment ( Figure 1). The incidence of ANSD, on the other hand, is not fully clear, with studies reporting incidences ranging from G + c.4091-1G > A in OTOF (OMIM 603681) for Family C, p.R65H + c.1638delT in TBC1D24 (OMIM 613577) for Family D, and p.A255V + p.R663W in LARS2 (OMIM 604544) for Family E ( Table 1). ( 2), who found that 10 individuals had abnormal peripheral auditory neural transmission but normal outer hair cell function. The first case of ANSD was diagnosed by Starr et al. Results: We analyzed nine cases of patients with ANSD with normal CMs/DPOAE and abnormal ABR, discovered three novel mutants of the OTOF gene that are known to cause ANSD, and six cases of other gene mutations including TBC1D24, LARS2, TIMM8A, MITF, and WFS1.Ĭonclusion: Our results extend the mutation spectrum of the OTOF gene and indicate that the genetic etiology of ANSD may be related to gene mutations of TBC1D24, LARS2, TIMM8A, MITF, and WFS1.Īfferent nerve conduction problems combined with the proper operation of outer hair cells enduring otoacoustic emissions (OAE) and/or cochlear microphonics (CMs) are the hallmark symptoms of auditory neuropathy spectrum disease (ANSD) ( 1). Subsequently, using a mini-gene assay, we examined the function of a novel splice site mutant of OTOF. For candidate pathogenic genes, we performed co-segregation among all family members of the pedigrees. Genomic DNA extracted from their peripheral blood was examined by next-generation sequencing (NGS) for a gene panel to identify any potential causal variations.
Methods: Nine probands have been identified as ANSD based on the results of the ABR tests and DPOAE/CMs. To study the etiology of ANSD, we collected 9 probands with ANSD diagnosed in the clinic and performed targeted next-generation sequencing.
To date, 13 genes identified as potentially causing ANSD have been documented. Objective: Auditory neuropathy spectrum disease (ANSD) is caused by both environmental and genetic causes and is defined by a failure in peripheral auditory neural transmission but normal outer hair cells function.
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