Mutational analysis of the SLC26A4 gene in Chinese sporadic nonsyndromic hearing-impaired children

China Rehabilitation and Research Center for Deaf Children, Beijing 100029, People's Republic of China.
International journal of pediatric otorhinolaryngology (Impact Factor: 1.19). 07/2012; 76(10):1474-80. DOI: 10.1016/j.ijporl.2012.06.027
Source: PubMed


To investigate the mutations of SLC26A4 gene and the relevant phenotype in Chinese sporadic nonsyndromic hearing-impaired children.
195 Chinese sporadic nonsyndromic hearing-impaired children were subjected to microarray-based mutation detection for 9 hot spot mutations in four of the most common deafness-related genes (GJB2, SLC26A4, GJB3, and 12s rRNA). Subsequently, twenty-one patients with one SLC26A4 mutation detected by microarray were subjected to sequencing analysis of the whole SLC26A4 coding region and the splice sites in order to identify the second mutant allele. The inner ear malformation and hearing loss level were compared among different genotypes.
The incidence of genetic mutations was found to be 43.59% (85/195) in this patient group using CapitalBio Deafness Gene Mutation Detection Array Kit. A total of 34 children (17.44%) were found carrying the mutant SLC26A4 sequences. Thirteen (6.67%) children carried two mutant alleles of SLC26A4 and 21 (10.77%) children carried one mutant allele of SLC26A4. After the application of subsequent sequencing analysis, 13 mutational variants including 4 novel variants, two missense (p.D661G, p.N457D), one splice site mutation (IVS15+1G>A) and one frameshift mutation (624_632del9insACTTGGC), were identified in SLC26A4 gene in 15 of the 21 previously monoallelic patients. No second mutation was identified in the remaining 6 children. Biallelic mutations of SLC26A4 were identified in 20 of 21 children with enlarged vestibular aqueduct.
Our results demonstrated that genetic factors were important causes for sporadic nonsyndromic hearing loss in Chinese pediatric cases. Mutation of SLC26A4 is one of the major genetic causes in nonsyndromic hearing loss with inner ear malformation. IVS7-2A>G, 2168A>G and 1229C>T were the most frequent mutations identified in our studies. The combination of microarray testing and sequencing analysis is a useful and high-throughput method for the diagnosis of genetic hearing loss.

13 Reads
  • Source
    • "The molecular diagnosis of hearing impairment associated with the SLC26A4 gene is reliable because deafness is caused by homozygous or compound heterozygous SLC26A4 mutations [6,23]. Previous studies [13,24,25]. suggested that SLC26A4 c.919-2A>G is the most frequent mutation in Taiwan and mainland China, and that less-frequent mutations of other exons may be detected by direct DNA sequence analysis [26]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Mutations in the SLC26A4 gene, which encodes the anion transporter, pendrin, are a major cause of autosomal recessive non-syndromic hearing loss (NSHL) in some Asian populations. SLC26A4 c.919-2A>G (IVS7-2A>G) is the most common mutation in East Asian deaf populations. To provide a basis for improving the clinical diagnosis of deaf patients, we evaluated 80 patients with the SLC26A4 c.919-2A>G monoallelic mutation from 1065 hearing-impaired subjects and reported the occurrence of a second mutant allele in these patients. Methods The occurrence of a second mutant allele in these 80 patients with a single c.919-2A>G mutation was investigated. Mutation screening was performed by bidirectional sequencing in SLC26A4 exons 2 to 6 and 9 to 21. Results We found that 47/80 patients carried another SLC26A4 c.919-2A>G compound mutation. The five most common mutations were: p.H723R, p.T410M, 15+5G>A (c.1705+5G>A), p.L676Q and p.N392Y. We found a Chinese-specific SLC26A4 mutation spectrum and an associated SLC26A4 contribution to deafness. Conclusion Our study illustrates that mutation analysis of other SLC26A4 exons should be undertaken in deaf patients with a single heterozygous SLC26A4 mutation. Moreover, a model of compound heterozygosity may partially explain the disease phenotype.
    Journal of Translational Medicine 11/2012; 10(1):225. DOI:10.1186/1479-5876-10-225 · 3.93 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To investigate the mutations in the SLC26A4 gene in a Chinese patient with Pendred syndrome. The diagnosis of Pendred syndrome was confirmed by the family history, pure tone audiogram, perchlorate discharge test (PDT), and computed tomography (CT) of the temporal bone. DNA extraction, PCR and DNA sequencing were performed according to standard procedures. Mutations in the SLC26A4 gene were compared with 100 unrelated subjects to exclude common polymorphism. Splice-site mutation was further confirmed by restriction enzyme length polymorphism (RFLP) with the specifically designed primers. The proband presented with typical features of bilateral sensorineural deafness since childhood and goiter development in the early adulthood. Thyroid studies disclosed euthyroidism with elevated thyroglobulin, but negative for PDT. Marked enlargement of bilateral vestibular aqueduct (>1.5mm) was found by CT of the temporal bone. A novel SLC26A4 splice-site mutation c.1263+1G>A (IVS10+1G>A) was identified in compound heterozygosity with the missense mutation c.1079C>T (p.A360V) in the proband. Both mutations were not found in the 100 unrelated Chinese. Our results support previous findings that Pendred syndrome can be caused by compound heterozygous mutation in the SLC26A4 gene, in which IVS10+1G>A is a novel pathogenic mutation.
    International journal of pediatric otorhinolaryngology 07/2013; 77(9). DOI:10.1016/j.ijporl.2013.06.017 · 1.19 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Recessive mutations in SLC26A4 and in rarer cases double heterozygous mutations of FOXI1/SLC26A4 and KCNJ10/SLC26A4 lead to hearing impairment associated with enlarged vestibular aqueduct (EVA), the most common inner ear malformation. In our large cohort study, we addressed several important questions to the molecular etiology of this disorder. The overall prevalence of SLC26A4 mutations in nonsyndromic childhood sensorineural hearing loss (11.2%, 37/330) were determined by sequencing of SLC26A4 in 330 hearing impaired children who did not undergo inner ear radiologic imaging prior to their genetic test. The penetrance of EVA in bi-allelic SLC26A4 mutation carriers (100%, 37/37) was determined by follow-up computed tomography scanning. Combined with the study of 140 additional probands diagnosed with nonsyndromic EVA, we characterized the mutation spectrum of SLC26A4 in East China, which consisted of 19 novel SLC26A4 mutations and differed from those reported in other regions of China. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 09/2013; 161(9). DOI:10.1002/ajmg.a.36068 · 2.16 Impact Factor
Show more