Novel mutations in the SLC26A4 gene

Audiology Department - Giovecca 203, 44121, University of Ferrara, Italy.
International journal of pediatric otorhinolaryngology (Impact Factor: 1.19). 06/2012; 76(9):1249-54. DOI: 10.1016/j.ijporl.2012.05.014
Source: PubMed


Mutations in the SLC26A4 gene (7q22.3-7q31.1) are considered one of the most common causes of genetic hearing loss. There are two clinical forms related to these mutations: syndromic and non-syndromic deafness. The first one is named Pendred Syndrome (PS) when deafness is associated with thyroid goiter; the second is called DFNB4, when no other symptoms are present. Both are transmitted as an autosomal recessive trait, but simple heterozygotes can develop both forms of deafness. Actually it is thought that Pendred Syndrome occurs when both alleles of SLC26A4 gene are mutated; DFNB4 seems due to monoallelic mutations. PS and DFNB4 can be associated with inner ear malformations. In most of the cases (around 80%), these consist in Enlarged Vestibular Aqueduct (EVA). EVA can also be present without SLC26A4 mutations. Understanding the role of new SLC26A4 variants should facilitate clinical assessment, as well as diagnostic and therapeutic approaches. This investigation aims to detect and report genetic causes of two unrelated Italian boys with hearing loss.
Patients and family members underwent clinical, audiological and genetic evaluations. To identify genetic mutations, DNA sequencing of SLC26A4 gene (including all 21 exons, exon-intron boundaries and promoter region) was carried out.
Both probands were affected by congenital, progressive and fluctuating mixed hearing loss. Temporal bone imaging revealed a bilateral EVA with no other abnormalities in both cases. Probands were heterozygotes for previously undescribed mutations in the SLC26A4 gene: R409H/IVS2+1delG (proband 1) and L236P/K590X (proband 2). No other mutations were detected in GJB2, GJB6 genes or mitochondrial DNA (mit-DNA).
The IVS2+1delG and K590X mutations have not yet been described in literature but there is some evidence to suggest that they have a pathological role. The results underlined the importance of considering the complete DNA sequencing of the SLC26A4 gene for differential molecular diagnosis of deafness, especially in those patients affected by congenital, progressive and fluctuating mixed hearing loss with bilateral EVA.

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Available from: Alessandro Castiglione, Oct 02, 2015
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    • "Coyle et al. (1998) reported four mutations (p.L236P, p.T416P, p.E384G and IVS8 + 1G > A) in SCL26A4 gene in northern Europe (16). Busi et al. (2012) reported two novel mutation (IVS2+1delG and K590X) in SCL26A4 gene and there is no other mutation in GJB2, GJB3, GJB6 and mtDNA (17). "
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    ABSTRACT: Aim: This study aimed to investigate the molecular testing of congenital hearing loss by using next generation sequencing technology. Pendred syndrome (PS) is described by severe bilateral sensorineural hearing loss with goiter. The mutations of SCL26A4 gene can cause PS. Material and Method: We evaluated the feasibility of target-enrichment and massive parallel sequencing technologies to interrogate all mutations of genes (GJB2, GJB3, GJB6, SLC26A4 and for the mitochondrial mutation A1555G) implicated in NSHL, we performed molecular analyses of 14 NSHL families and patients by using Miseq system (Illumina Inc.). Next-Generation sequencing (NGS) technologies provide specificity, sensitivity and reproducibility at levels sufficient to perform genetic diagnosis of hearing loss. Results: We found two different mutations in SCL26A4 gene such as F354S and I588T in both consanguineous families as diagnosed with Pendred syndrome and we reported a novel mutation in SCL26A4 gene. We found no mutation in GJB2, GJB3, GJB6 gene and A1555G mtDNA in this study. Conclusion: These results highlight the benefits using targeted gene panels with NGS technologies in the molecular analysis of nonsyndromic, congenital hearing loss patients. This study assessed the frequency of deafness genes in Turkish children with congenital hearing loss who had been treated with cochlear implantation, and we found a novel mutation (I588T) in SLC26A4 gene. Key Words: Pendred syndrome, Congenital Hearing Loss, Next-Generation sequencing.
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    • "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]. In the present study, 58.8% of patients carrying a heterozygous c.919-2A>G mutation (47/80) had a definite form of SNHL caused by a SLC26A4 mutation. "
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    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
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    ABSTRACT: Objective: Enlarged vestibular aqueduct is the most common inner ear malformation in individuals with sensorineural hearing loss. Mutations in SLC26A4 can cause non-syndromic EVA. To date, more than 170 SLC26A4 mutations have been described. The aim of the present study was to detect and report genetic causes of four unrelated Chinese families with hearing loss. Methods: We evaluated 4 families presenting bilateral enlarged vestibular aqueducts and describe the clinical and molecular characteristics of 5 patients. Results: The SLC26A4 gene was sequenced in 23 members of these 4 Chinese families with EVA, and the patients were found to carry 4 compound heterozygous mutations, p.G197R and p.S391R, IVS7-2A>G, p.I188T and c.1746 del G, p.V659L and p.T410M, and p.T94I and p.G197R, none of which have been reported previously. Conclusions: These results emphasize the necessity of considering the complete DNA sequencing of the SLC26A4 gene in molecular diagnosis of deafness, especially when phenotypes such as congenital, invariable, and progressive hearing loss with EVA are present.
    International journal of pediatric otorhinolaryngology 02/2013; 77(4). DOI:10.1016/j.ijporl.2013.01.002 · 1.19 Impact Factor
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