Abstract
BackgroundRecessive mutations of coding regions and splice sites of the SLC26A4 gene cause hearing loss with enlargement of the vestibular aqueduct (EVA). Some patients also have a thyroid iodination defect that can lead to multinodular goiter as part of Pendred syndrome. A haplotype of variants upstream of SLC26A4, called CEVA, acts as a pathogenic recessive allele in trans to mutations affecting the coding regions or splice sites of SLC26A4. Our first hypothesis is that CEVA, acting as a pathogenic recessive allele, is correlated with a less severe phenotype than mutations affecting the coding regions and splice sites of SLC26A4. Our second hypothesis is that CEVA acts as a modifier of the phenotype in patients with EVA caused by mutations affecting the coding regions or splice sites of both alleles of SLC26A4 or EVA caused by other factors.MethodsThis was a prospective cohort study of 114 individuals and 202 ears with EVA. To test our first hypothesis, we compared the thyroid and auditory phenotypes of subjects with mutations affecting coding regions of both alleles of SLC26A4 with those of subjects carrying CEVA in trans to mutations affecting the coding regions. To test our second hypothesis, we compared the phenotypes associated with the presence versus absence of CEVA among subjects with no coding region mutations, as well as among subjects with mutations affecting coding regions of both alleles.ResultsSubjects carrying CEVA in trans to a mutation of SLC26A4 have a normal thyroid phenotype and less severe hearing loss in comparison to individuals with mutations affecting coding regions of both alleles of SLC26A4. In subjects with no mutant alleles of SLC26A4, hearing loss was more severe in subjects who carry the CEVA haplotype in comparison to non-carriers. There was no correlation of CEVA with the phenotype of subjects with mutations affecting coding regions of both alleles.ConclusionsCEVA, acting as a likely pathogenic recessive allele, is associated with a less severe phenotype than alleles with a mutation affecting the coding regions or splice sites of SLC26A4. CEVA may act as a genetic modifier in patients with EVA caused by other factors.
Highlights
Recessive mutations of coding regions and splice sites of the SLC26A4 gene cause hearing loss with enlargement of the vestibular aqueduct (EVA)
To test the hypothesis that Caucasian EVA (CEVA), acting as a recessive mutant allele, is correlated with a less severe phenotype than mutations affecting the coding regions or splice sites of SLC26A4, we compared the phenotypes of mutations of SLC26A4 (M2) subjects without CEVA to those of M1 subjects with CEVA in trans to an allele with the reference haplotype and a mutation affecting the coding regions or splice sites but no CEVA
Linear regression analysis determined that among M2 R/R and M1 C/R patients, there is a significant negative correlation between hearing loss and CEVA, adjusting for age, sex, and laterality (p < 0.001; R2 = 3.94). These results indicate that, as a recessive Mendelian allele in trans to an allele with a mutation of the coding regions or splice sites of SLC26A4, an allele with CEVA but no coding region or splice site mutations is associated with a normal thyroid phenotype and less severe hearing loss in comparison to alleles with a mutation of the coding regions or splice sites and the reference haplotype
Summary
Recessive mutations of coding regions and splice sites of the SLC26A4 gene cause hearing loss with enlargement of the vestibular aqueduct (EVA). Our first hypothesis is that CEVA, acting as a pathogenic recessive allele, is correlated with a less severe phenotype than mutations affecting the coding regions and splice sites of SLC26A4. Our second hypothesis is that CEVA acts as a modifier of the phenotype in patients with EVA caused by mutations affecting the coding regions or splice sites of both alleles of SLC26A4 or EVA caused by other factors. Mutations of SLC26A4 can cause bilateral EVA and a thyroid iodination defect that can lead to multinodular goiter as part of Pendred syndrome (PS) (OMIM 274600) [3]. It was recently reported that some specific mutations are correlated with hearing loss progression or severity in Korean populations [8, 9]
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