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 "hearing loss" symptom

22q11.2 deletion syndrome

achondroplasia

adrenomyeloneuropathy

alexander disease

benign recurrent intrahepatic cholestasis

canavan disease

cohen syndrome

congenital toxoplasmosis

dentinogenesis imperfecta

fabry disease

familial mediterranean fever

heparin-induced thrombocytopenia

hirschsprung disease

holt-oram syndrome

homocystinuria without methylmalonic aciduria

hydrocephalus with stenosis of the aqueduct of sylvius

kabuki syndrome

kallmann syndrome

neonatal adrenoleukodystrophy

pendred syndrome

von hippel-lindau disease

wolf-hirschhorn syndrome

This symptom has already been validated