Novel mutations in the SLC26A4 gene.

Audiology Department - Giovecca 203, 44121, University of Ferrara, Italy.
International journal of pediatric otorhinolaryngology (Impact Factor: 0.85). 06/2012; 76(9):1249-54. DOI: 10.1016/j.ijporl.2012.05.014
Source: PubMed

ABSTRACT 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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    ABSTRACT: Hearing impairment is one of the commonest clinical conditions. It has been estimated that approximately 1 in 10 persons has hearing concerns. Further epidemiological studies have found that the percentage of the general population with hearing loss greater than 45 dB HL and 65 dB HL is 1.3% and 0.3%, respectively, between 30 and 50 years of age; and 2.3% and 7.4% between 60 and 70 years of age. The prevalence of childhood and adolescent hearing loss is around 3%. At birth, between one and two out of 1000 newborns are affected by hearing loss of such a degree as to require treatment (auditory training and rehabilitation, hearing aids or cochlear implantation). To summarize, hearing impairment affects up to 30% of the international community and estimates indicate that 70 million persons are deaf. The causes of hearing loss differ and they can vary in severity and physiopathology. In many cases it is not possible to define a definite aetiology. Nevertheless, it is known that most are due to a genetic cause and among these the majority appear in a non-syndromic form. The aetiology of hearing loss in children is unknown in 40% of cases, genetic non-syndromic in 30%, and genetic syndromic in 3–5%. The two most common genes involved in hearing loss are GJB2 and SLC26A4. Mutations in these genes can be responsible for syndromic hearing loss, as keratitis ichthyosis deafness (KID) and Pendred syndromes, respectively, or non-syndromic hearing loss (as DFNB1 and DFNB4, respectively). DFNB1 with GJB2 mutations is the most common non-syndromic form and Pendred syndrome is the most common syndromic form. Neither of these last two is usually characterized by congenital macroscopic dysmorphic features, and affected children can be generally considered as well babies. Nonetheless, 2–4% of live births have congenital malformations, most commonly caused by multifactorial defects, followed by chromosomal disorders, single gene mutations and teratogens (alcohol, drugs). Some of these conditions could directly affect the auditory system and be responsible for sensorineural, conductive or mixed hearing loss. The London Dysmorphology Database lists approximately 400 syndromes that include hearing loss among the clinical features. Other conditions such as cystic fibrosis are not usually responsible for hearing loss but they can indirectly affect the auditory system as a consequence of the management of the disease. Other systemic disorders can lead to hearing impairment when the disease involves a part of the auditory system from the external ear to the auditory cortex. From this standpoint there are a huge number of syndromes or conditions that can directly or indirectly cause hearing impairment. They can be responsible for congenital or prelingual, progressive and post-lingual hearing loss, with sensorineural, mixed or conductive deficits. In this updating research we have focused on syndromic forms that are known to be associated with hearing loss or that directly affect the auditory system. Some conditions of particular interest, or with high incidence, are also included.
    Hearing, Balance and Communication. 08/2013;
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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. · 3.46 Impact Factor


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