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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. [Copyright &y& Elsevier]

Congenital microphthalmia (CMIC) is a common developmental ocular disorder characterized by a small, and sometimes malformed, eye. Posterior microphthalmia (PM) and nanophthalmia are two rare subtypes of isolated CMIC characterized by extreme hyperopia due to short axial length and elevated lens/eye volume ratio. While nanophthalmia is associated with a reduced size in both anterior and posterior segments, PM involves a normal-size anterior chamber but a small posterior segment. Several genes encoding transcription and non-transcription regulators have been identified in different forms of CMIC. MFRP gene mutations have, for instance, been associated with nanophthalmia, and mutations in the recently identified PRSS56 gene have been linked to PM. So far, these two forms of CMIC have been associated with 9 mutations in PRSS56. Of particular interest, a c.1059_1066insC mutation has recently been reported in four Tunisian families with isolated PM and one Tunisian family with nanophthalmia. Here, we performed a genome-wide scan using a high density single nucleotide polymorphism (SNP) array 50 K in a large consanguineous Tunisian family (PM7) affected with PM and identified the same causative disease mutation. A total of 24 polymorphic markers spanning the PRSS56 gene in 6 families originating from different regions of Tunisia were analyzed to investigate the origin of the c.1059_1066insC mutation and to determine whether it arose in a common ancestor. A highly significant disease-associated haplotype, spanning across the 146kb of the 2q37.1 chromosome, was conserved in those families, suggesting that c.1059_1066insC arose from a common founder. The age of the mutation in this haplotype was estimated to be around 1850years. The identification of such ‘founder effects’ may greatly simplify diagnostic genetic screening and lead to better prognostic counseling. [ABSTRACT FROM AUTHOR]

Abstract: Autosomal recessive non-syndromic hearing loss (ARNSHL) is a genetically heterogenous disorder with 41 genes so far identified. Among these genes, ESRRB whose mutations are responsible for DFNB35 hearing loss in Pakistani and Turkish families. This gene encodes the estrogen-related receptor beta. In this study, we report a novel mutation (p.Y305H) in the ESRRB gene in a Tunisian family with ARNSHL. This mutation was not detected in 100 healthy individuals. Molecular modeling showed that the p.Y305H mutation is likely to alter the conformation of the ligand binding-site by destabilizing the coactivator binding pocket. Interestingly, this ligand-binding domain of the ESRRB protein has been affected in 5 out of 6 mutations causing DFNB35 hearing loss. Using linkage and DHPLC analysis, no more mutations were detected in the ESRRB gene in other 127 Tunisian families with ARNSHL indicating that DFNB35 is most likely to be a rare type of ARNSHL in the Tunisian population. [Copyright &y& Elsevier]