A commonSLC26A4-linked haplotype underlying non-syndromic hearing loss with enlargement of the vestibular aqueduct

Abstract

Background Enlargement of the vestibular aqueduct (EVA) is the most common radiological abnormality in children with sensorineural hearing loss. Mutations in coding regions and splice sites of the SLC26A4 gene are often detected in Caucasians with EVA. Approximately one-fourth of patients with EVA have two mutant alleles (M2), one-fourth have one mutant allele (M1) and one-half have no mutant alleles (M0). The M2 genotype is correlated with a more severe phenotype. Methods We performed genotype–haplotype analysis and massively parallel sequencing of the SLC26A4 region in patients with M1 EVA and their families. Results We identified a shared novel haplotype, termed CEVA (Caucasian EVA), composed of 12 uncommon variants upstream of SLC26A4. The presence of the CEVA haplotype on seven of ten ’mutation-negative’ chromosomes in a National Institutes of Health M1 EVA discovery cohort and six of six mutation-negative chromosomes in a Danish M1 EVA replication cohort is higher than the observed prevalence of 28 of 1006 Caucasian control chromosomes (p<0.0001 for each EVA cohort). The corresponding heterozygous carrier rate is 28/503 (5.6%). The prevalence of CEVA (11 of 126) is also increased among M0 EVA chromosomes (p=0.0042). Conclusions T he CEVA haplotype causally contributes to most cases of Caucasian M1 EVA and, possibly, some cases of M0 EVA. The CEVA haplotype of SLC26A4 defines the most common allele associated with hereditary hearing loss in Caucasians. The diagnostic yield and prognostic utility of sequence analysis of SLC26A4 exons and splice sites will be markedly increased by addition of testing for the CEVA haplotype.

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

“…Given that one copy of WT‐pendrin gene is sufficient for supporting normal inner ear function, it seems unlikely that pendrin variants with WT‐like transport activities (e.g., p.Ser49Arg, p.Leu117Phe, p.Val163Ile, p.Asp266Asn, p.Thr307Ala, p.Asn324Tyr, p.Phe354Ser, p.Arg470His) are pathogenic. We speculate that these are nonpathogenic functional variants that cosegregate with a truly pathogenic genetic alteration such as those reported in previous studies (Ben Said et al, ; Chattaraj et al, ; Pique et al, ; Yang et al, ). This possibility also needs to be entertained for biallelic pendrin variants that only partly impair the overall pendrin‐mediated transport activity, especially when the sums of the transport activities of the two pendrin variants are comparable to or exceeds that of WT.…”

Global genetic insight contributed by consanguineous Pakistani families segregating hearing loss

“…Variants in SLC26A4 alone account for 16.9% (95% CI: 13.2–21.4%) of variants in our 321 families. SLC26A4 encodes pendrin, a transmembrane anion exchanger for chloride, iodide, bicarbonate, and other ions, essential for the development of inner ear and ionic homeostasis (Chattaraj et al., ; Choi et al., ; Everett et al., ; Rehman, Friedman, & Griffith, ). Consistent with our previous findings (Anwar et al., ), c.716T>A [p.(Val239Asp)] is the prevalent variant responsible for SLC26A4 ‐associated HL in Pakistani families.…”

Functional Testing of SLC26A4 Variants—Clinical and Molecular Analysis of a Cohort with Enlarged Vestibular Aqueduct from Austria

“…For example, sequence alterations within the promoter or cis-regulatory (enhancer) regions leading to a reduced transcription may per se be insufficient to determine a pathological phenotype, but can be pathogenic in combination with another dysfunctional allele. These sequence alterations may reside in upstream regions distant from SLC26A4 , intergenic regions or even other genes [ 50 ]. For this patient, the only other sequence alteration in SLC26A4 with an allele frequency <1%, of which the clinical significance was not assessed, was found in the 3’UTR (g.55910G>A, rs375630290, Table S3 ).…”