Correlation between genotype and phenotype in patients with bi‐allelic SLC26A4 mutations

Abstract

Mutation of SLC26A4 is the most common cause of prelingual hearing loss in East Asia. Patients with SLC26A4 mutations have variable phenotypes ranging from non-syndromic hearing loss to Pendred syndrome. Here, we analyzed the correlation between genotype and various inner ear phenotypes and found a possible underlying mechanism. This study included 111 patients with bi-allelic SLC26A4 mutations who had bilateral enlarged vestibular aqueduct (EVA) and hearing loss. p.H723R (61%), c.919-2A>G (24%), and p.T410M (4%) were the most common mutations in Korean patients with EVAs. Residual hearing in patients with c.919-2A>G or p.T410M mutations was better than that of patients with p.H723R homozygous mutations. Interestingly, quantitative polymerase chain reaction showed normal pendrin transcript (6-17% of normal levels) was produced from patients with c.919-2A>G homozygous mutations. Surface expression ratio of pendrin and residual anion exchange activity were higher in cells transfected with p.T410M in comparison to cells transfected with p.H723R. These results suggest that there is a correlation between degree of residual hearing and the SLC26A4 genotype commonly found in the East Asian population.

Systematic quantification of the anion transport function of pendrin (SLC26A4) and its disease‐associated variants

“…In this study, we focused on 51 exonic single nucleotide variants found in the pendrin gene, which are presumed to cause missense changes (Table ). Among these, the effects of 22 variants (p.Leu117Phe, p.Pro123Ser, p.Met147Val, p.Thr193Ile, p.Val239Asp, p.Asp266Asn, p.Phe354Ser, p.Lys369Glu, p.Ala372Val, p.Asn392Tyr, p.Ser408Phe, p.Arg409His, p.Thr410Met, p.Thr416Pro, p.Leu445Trp, p.Gly497Ser, p.Tyr556Cys, p.C565Tyr, p.Ser657Asn, p.Ser666Phe, p.Thr721Met, and p.His723Arg) on the anion transport function of pendrin have been previously studied (Choi et al, ; Dai et al, ; de Moraes et al, ; Dossena, Bizhanova et al, ; Dossena, Nofziger et al, ; Gillam, Bartolone, Kopp, & Benvenga, ; Ishihara et al, ; Jung et al, ; Kuwabara et al, ; Lee et al, ; Muskett et al, ; Scott et al, ; Taylor, Metcalfe, Watson, Weetman, & Trembath, ; Yoon et al, ), whereas the remaining 29 await experimental characterization. All these missense variants, except for p.Ser408Phe that was identified in mice in a mutagenesis screen (Dror et al, ), were found in human patients (Stenson et al, ), of which p.Tyr214Cys, p.Thr410Lys, p.Val483Glu, and p.Leu703Pro are novel pendrin missense variants described for the first time in this report (Tables S1 and S2).…”

Nationwide population genetic screening improves outcomes of newborn screening for hearing loss in China

“…They are expected to develop hearing loss eventually because the penetrance of hearing loss in individuals with biallelic pathogenic variants in GJB2 or SLC26A4 on our screening panel is nearly complete taking into account variable age of onset. 22–24 Long-term longitudinal follow-up is necessary to document their hearing status. In the inconclusive group, 37 subjects were reported to have hearing loss.…”

Government-funded universal newborn hearing screening and genetic analyses of deafness predisposing genes in Taiwan

“…Kim et al reported that a substantial portion of subjects with SLC26A4 mutations escape from universal newborn hearing screening [46]. Especially, c.919-2A>G, which is very frequent in Chinese and Taiwanese was reported to have a better residual hearing than p.H723R [47]. Therefore, long-term follow up of this cohort is necessary.…”