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Background  Recessive 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.    Methods  This 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.    Results  Subjects 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.    Conclusions  CEVA, 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.

SLC26A4-linked CEVA haplotype correlates with phenotype in patients with enlargement of the vestibular aqueduct