Anti-GJB2 (internal region) polyclonal antibody

As the number of genes identified for linkage to hearing loss has been increasing and more public databases have become available, we aimed to systematically evaluate all variants reported for nonsyndromic hearing loss (NSHL) based on their allele frequencies (AFs) in the general population. Among the 3,549 variants in 97 NSHL genes reported as pathogenic/likely pathogenic in ClinVar and HGMD, 1,618 were found in public databases (gnomAD, ExAC, EVS, and 1000G). To evaluate the pathogenicity of these variants, we employed AF thresholds and NSHL-optimized ACMG guidelines. AF thresholds were determined using a high-resolution variant frequency framework and Hardy-Weinberg equilibrium calculation: 0.6% and 0.1% for recessive and dominant genes, respectively. Filtering AFs of variants linked to NSHL were obtained based on AFs reported in gnomAD and ExAC. We found that 48 variants in 23 genes had filtering AFs above the suggested thresholds and assumed that these variants might be benign based on their filtering AFs. 47 variants, except for one notorious high-frequency GJB2 mutation (c.109G > A; p.Val37Ile), were confirmed to be benign/likely benign by the NSHL-optimized ACMG guidelines. The proposed systematic approach will aid in precise evaluation of NSHL variant pathogenicity in the context of filtering AFs,( )AF thresholds, and NSHL-specific ACMG guidelines, thus improving NSHL diagnostics.

The diagnosis of the genetic etiology of deafness contributes to the clinical management of patients. We performed the following four genetic tests in three stages for 52 consecutive deafness subjects in one facility. We used the Invader assay for 46 mutations in 13 genes and Sanger sequencing for the GJB2 gene or SLC26A4 gene in the first-stage test, the TaqMan genotyping assay in the second-stage test and targeted exon sequencing using massively parallel DNA sequencing in the third-stage test. Overall, we identified the genetic cause in 40% (21/52) of patients. The diagnostic rates of autosomal dominant, autosomal recessive and sporadic cases were 50%, 60% and 34%, respectively. When the sporadic cases with congenital and severe hearing loss were selected, the diagnostic rate rose to 48%. The combination approach using these genetic tests appears to be useful as a diagnostic tool for deafness patients. We recommended that genetic testing for the screening of common mutations in deafness genes using the Invader assay or TaqMan genotyping assay be performed as the initial evaluation. For the remaining undiagnosed cases, targeted exon sequencing using massively parallel DNA sequencing is clinically and economically beneficial.