Landa P, etal., BMC Med Genet. 2013 Aug 21;14:85. doi: 10.1186/1471-2350-14-85.
BACKGROUND: Pendred syndrome is a common autosomal recessive disorder causing deafness. Features include sensorineural hearing impairment, goitre, enlarged vestibular aqueducts (EVA) and occasionally Mondini dysplasia. Hearing impairment and EVA may occur in the absence of goitre or thyroid dyshormo
nogensis in a condition known as non-syndromic EVA. A significant number of patients with Pendred syndrome and non-syndromic EVA show only one mutation in SLC26A4. Two genes, KCNJ10, encoding an inwardly rectifying potassium channel and FOXI1, a transcriptional factor gene, are thought to play a role in the disease phenotypes. METHODS: Using Polymerase Chain Reaction and Sanger sequencing, sixty-eight patients with monoallelic mutations of SLC26A4 were tested for mutations in KCNJ10 and FOXI1. RESULTS: Two variants were observed in the KCNJ10 gene, p.Arg271Cys in three patients and p.Arg18Gln in one patient; only one variant, p.Arg123Trp was observed in the FOXI1 gene in a single patient. Both p.Arg271Cys and p.Arg18Gln are likely to be polymorphisms as judged by their frequency in the general population. CONCLUSION: Therefore we found no evidence for a significant association between mutations of KCNJ10 and FOXI1 with SLC26A4. It was also observed that the variant, p.Arg271Cys in KCNJ10, previously thought to have a protective effect against seizure susceptibility, was found in a patient with Pendred syndrome with co-existing epilepsy.
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, hampe
ring 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.
OBJECTIVE: To investigate the implication of SLC26A4, FOXI and KCNJ10 genes in unilateral hearing impairment associated with ipsilateral inner ear malformation (Enlargement of the vestibular aqueduct and/or Mondini dysplasia). METHODS: We have gathered 25 patients presenting unilateral hearing impa
irment and ipsilateral enlarged vestibular aqueduct. For each of the patients, we have analyzed SLC26A4, FOXI1 and KCNJ10 genes sequences. RESULTS: The analysis of SLC26A4 revealed only eight heterozygous SLC26A4 sequence variants, three of them being novel (p.Met147Ile, p.Asn538Asn and p.Leu627Arg). None of the patients carried a second mutation on the other allele. Moreover, the SLC26A4 locus was excluded by segregation analysis in two families. No mutations were present in FOXI1 and KCNJ10 genes. CONCLUSIONS: Together, these data suggest that SLC26A4, FOXI1 and KCNJ10 are not major determinants in unilateral deafness and enlarged vestibular aqueduct compared with their implication in Pendred syndrome and non-syndromic bilateral enlarged vestibular aqueduct.
Chen K, etal., Otolaryngol Head Neck Surg. 2012 Jun;146(6):972-8. doi: 10.1177/0194599812439670. Epub 2012 Mar 12.
OBJECTIVE: Bilateral nonsyndromic sensorineural hearing loss associated with inner ear malformation is closely related to genetics. SLC26A4 is considered to be the major involved gene. Recently, FOXI1 and KCNJ10 mutations have been linked to enlarged vestibular
aqueducts and GJB2 mutations linked to temporal bone malformation. The authors aimed to investigate the mutation spectrums of these genes in Chinese patients with bilateral hearing impairment associated with inner ear malformation. STUDY DESIGN: Cross-sectional study. SETTING: Affiliated hospital of the university. SUBJECTS AND METHODS: The authors analyzed the GJB2, SLC26A4, FOXI1, and KCNJ10 gene sequences in 43 patients presenting with bilateral hearing impairment associated with inner ear malformation using pyrosequencing and direct DNA sequencing. RESULTS: In total, 74.4% (32/43) of patients carried at least 1 of 14 pathogenic SLC26A4 mutations, including 6 novel mutations and 4 polymorphisms. Patients with enlarged vestibular aqueducts had a higher rate of SLC26A4 mutation than Mondini dysplasia patients. No FOXI1 or KCNJ10 potential pathogenic mutation was present, and GJB2 biallelic pathogenic mutations were uncommon (2.3%; 1/43). No significant correlation was observed between the genotype and phenotype of SLC26A4 mutations. CONCLUSION: SLC26A4 accounts for 74.4% of inner ear malformations in our cohort, whereas FOXI1, KCNJ10, and GJB2 mutations are not common. Other possible genes or external factors may contribute to this multibranch abnormality.
