title: Segregation of a new mutation in SLC26A4 and p.E47X mutation in GJB2 within a consanguineous Tunisian family affected with Pendred syndrome.
abstract: OBJECTIVE
  Recessive mutations of the SLC26A4 (PDS) gene on chromosome 7q31 can cause sensorineural hearing loss with goiter (Pendred syndrome) or non-syndromic autosomal recessive hearing loss (DFNB4). Furthermore, mutations in the GJB2 gene results in autosomal recessive (DFNB1) and dominant (DFNA3) non-syndromic hearing loss. The aim of the present study was to characterize a family with Pendred syndrome affected by severe to profound HL and presenting goiter.
  
  
  METHODS
  Affected members underwent detailed audiologic examination and characterization. DNA samples from family members were genotyped with polymorphic microsatellite markers and sequencing of the SLC26A4 and GJB2 genes was performed. A total of 25 families with non-syndromic hearing loss were screened for the common p.E47X mutation in the GJB2 gene by direct dideoxy sequencing.
  
  
  RESULTS
  Genetic microsatellite analysis showed linkage to the 7q22-q31 chromosomal region and mutation analysis revealed a novel frameshift mutation (c.451delG) in the SLC26A4 gene. Screening of the GJB2 gene in one patient, displayed a homozygous p.E47X mutation, together with a heterozygous c.451delG mutation. Screening of 25 families with HL showed frequent segregation of the p.E47X mutation, which was homozygous in five of these families. Haplotype analysis using microsatellite markers and single nucleotide polymorphisms (SNPs) closely flanking the GJB2 gene, revealed the presence of two disease-associated-haplotypes suggesting the presence of at least, two founder effects carrying the p.E47X non-sense mutation in the Tunisian population.
  
  
  CONCLUSIONS
  The segregation of both SLC26A4 and GJB2 mutations in the family illustrates once again the unexpected intra-familial genetic heterogeneity in consanguineous families and highlights the difficulty of genetic counselling in such families. In addition, our results disclose the existence of founder effects in the Tunisian population.
authors.affiliation: Laboratoire de microorganismes et biomolécules, Centre de Biotechnologie de Sfax, Sfax, Tunisia.
authors.forename: Mariem
authors.initials: M
authors.lastname: Ben Said
authors.forename: Houria
authors.initials: H
authors.lastname: Dhouib
authors.forename: Zeineb
authors.initials: Z
authors.lastname: BenZina
authors.forename: Abdelmoneem
authors.initials: A
authors.lastname: Ghorbel
authors.forename: Felipe
authors.initials: F
authors.lastname: Moreno
authors.forename: Saber
authors.initials: S
authors.lastname: Masmoudi
authors.forename: Hammadi
authors.initials: H
authors.lastname: Ayadi
authors.forename: Mounira
authors.initials: M
authors.lastname: Hmani-Aifa
mesh_terms: D000328:Adult; D002648:Child; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics*; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods; D005838:Genotype; D006044:Goiter, Nodular / Q000175:diagnosis / Q000235:genetics*; D006319:Hearing Loss, Sensorineural / Q000175:diagnosis / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D011110:Polymorphism, Genetic; D000076988:Sulfate Transporters; D014416:Tunisia; D055815:Young Adult
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; D026901:Membrane Transport Proteins; C085609:SLC26A4 protein, human; D000076988:Sulfate Transporters; D000072259:Connexin 26