Novel mutations in the SLC26A4 gene.

[pendred syndrome]

Mutations in the SLC 26 A 4 gene (7 q 22 .3 -7 q 31 .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 DFNB 4 , 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 SLC 26 A 4 gene are mutated ; DFNB 4 seems due to monoallelic mutations . PS and DFNB 4 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 SLC 26 A 4 mutations . Understanding the role of new SLC 26 A 4 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 SLC 26 A 4 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 SLC 26 A 4 gene : R 409 H /IVS 2 +1 delG (proband 1 ) and L 236 P /K 590 X (proband 2 ). No other mutations were detected in GJB 2 , GJB 6 genes or mitochondrial DNA (mit-DNA ).The IVS 2 +1 delG and K 590 X 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 SLC 26 A 4 gene for differential molecular diagnosis of deafness , especially in those patients affected by congenital , progressive and fluctuating mixed hearing loss with bilateral EVA .

Diseases
Validation

Diseases presenting "goiter" symptom

cowden syndrome

familial mediterranean fever

kabuki syndrome

pendred syndrome

This symptom has already been validated