Phenotypic Analyses and Mutation Screening of the <i>SLC26A4</i> and <i>FOXI1</i> Genes in 101 Taiwanese Families with Bilateral Nonsyndromic Enlarged Vestibular Aqueduct (DFNB4) or Pendred Syndrome

Abstract

Recessive mutations in the SLC26A4 gene are responsible for nonsyndromic enlarged vestibular aqueduct (EVA) and Pendred syndrome. However, in some affected families, only 1 or 0 mutated allele can be identified, as well as no clear correlation between SLC26A4 genotypes and clinical phenotypes, hampering the accuracy of genetic counseling. To elucidate the genetic composition of nonsyndromic EVA and Pendred syndrome, we screened related genomic fragments, including the SLC26A4 coding regions, the SLC26A4 promoter and the FOXI1 transcription factor gene, in 101 Taiwanese families, and analyzed their phenotypic and genotypic results. Mutation screening in the SLC26A4 coding regions by direct sequencing and quantitative polymerase chain reaction detected 2 mutations in 63 (62%) families, 1 mutation in 24 (24%) families and no mutation in 14 (14%) families. The radiological findings, the presence of goiters and the audiological results were not different among probands (i.e. index cases of the families) with different SLC26A4 genotypes. Specifically, probands heterozygous for SLC26A4 mutations demonstrated clinical features indistinguishable from those of probands with 2 mutated alleles, implicating that there might be undetected mutations. However, except for a variant (c.–2554G>A of SLC26A4) with possible pathological consequences, no definite mutation was detected after extensive screening in the SLC26A4 promoter and FOXI1. In other words, in most Taiwanese families nonsyndromic EVA or Pendred syndrome might not result from aberrance in the transcriptional control of SLC26A4 by FOXI1. Meanwhile, exploration of undetected mutations in the SLC26A4 noncoding regions revealed 9 divergent haplotypes among the 21 no-mutation-detected SLC26A4 alleles of the c.919-2A>G heterozygotes, indicating that there might be no common and predominant mutations in the SLC26A4 introns.

<i>SLC26A4</i> Genotypes and Phenotypes Associated with Enlargement of the Vestibular Aqueduct

“…Yang et al described several EVA patients with a heterozygous SLC26A4 mutation in combination with a heterozygous hypo-functional variant of FOXI1 [51] or KCNJ10 [52]. However, these results have not been obtained in other studies of EVA cohorts [53][54][55] and the pathogenic potential of the reported FOXI1 and KCNJ10 variants remains uncertain [56,57].…”

Identification of Novel Functional Null Allele of <b><i>SLC26A4</i></b> Associated with Enlarged Vestibular Aqueduct and Its Possible Implication

“…Previously, it was suggested that a second undetected mutant allele of SLC26A4 in Caucasian M1 EVA subjects would encode some residual pendrin, leading to a less severe phenotype than the M2 EVA group [Choi et al, 2009a-c]. However, it is possible that this genotype-phenotype correlation does not apply to East Asian populations since some studies in these populations failed to delineate the same genotype-phenotype correlation [Miyagawa et al, 2014;Wu et al, 2010]. These studies showed a similar severity of clinical features between the M1 and M2 groups .…”

Mutation analysis of the SLC26A4, FOXI1 and KCNJ10 genes in individuals with congenital hearing loss

“…The autosomal recessive inheritance of PDS and DFNB4 is well established and yet, for many affected individuals, analysis of the coding sequences and splice sites of the SLC26A4 gene PrePrints has failed to identify one or both of the mutations required to cause these disorders (Campbell et al, 2001;Tsukamoto et al, 2003;Pryor et al, 2005;Albert et al, 2006;Yang et al, 2007;Wu et al, 2010). In fact, an analysis of six studies with a total enrollment of 769 hearing impaired probands with EVA, a non-pathognomonic clinical finding that is a hallmark of PDS and DFNB4, reveals that only 25% have biallelic SLC26A4 mutations ( Table 2).…”

“…However, a meta-analysis of published studies in PrePrints which FOXI1 and KCNJ10 were sequenced in SNHL patients with inner ear malformations does not support these frequencies ( the initial studies that implicated the genes in the digenic inheritance of PDS/DFNB4 (Yang et al, 2007;Yang et al, 2009). However, the actual contribution of FOXI1 and KCNJ10 mutations to SNHL may be more limited, as illustrated by several subsequent studies in which either no FOXI1 variants (Wu et al, 2010;Mercer, Mutton & Dahl, 2011;Lai et al, 2012;Chen et al, 2012;Chai et al, 2013), or no KCNJ10 variants (Mercer, Mutton & Dahl, 2011;Chen et al, 2012) were identified.…”