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Autosomal recessive retinitis pigmentosa (ARRP) is a genetically heterogeneous disorder. ARRP could be associated with extraocular manifestations that define specific syndromes such as Usher syndrome (USH) characterized by retinal degeneration and congenital hearing loss (HL). The USH type II (USH2) associates RP and mild-to-moderate HL with preserved vestibular function. At least three genes USH2A, the very large G-protein-coupled receptor, GPR98, and DFNB31 are responsible for USH2 syndrome. Here, we report on the segregation of non-syndromic ARRP and USH2 syndrome in a consanguineous Tunisian family, which was previously used to define USH2B locus. With regard to the co-occurrence of these two different pathologies, clinical and genetic reanalysis of the extended family showed (i) phenotypic heterogeneity within USH2 patients and (ii) excluded linkage to USH2B locus. Indeed, linkage analysis disclosed the cosegregation of the USH2 phenotype with the USH2C locus markers, D5S428 and D5S618, whereas the ARRP perfectly segregates with PDE6B flanking markers D4S3360 and D4S2930. Molecular analysis revealed two new missense mutations, p.Y6044C and p.W807R, occurring in GPR98 and PDE6B genes, respectively. In conclusion, our results show that the USH2B locus at chromosome 3p23–24.2 does not exist, and we therefore withdraw this locus designation. The combination of molecular findings for GPR98 and PDE6B genes enable us to explain the phenotypic heterogeneity and particularly the severe ocular affection first observed in one USH2 patient. This report presents an illustration of how consanguinity could increase familial clustering of multiple hereditary diseases within the same family.European Journal of Human Genetics (2009) 17, 474–482; doi:10.1038/ejhg.2008.167; published online 15 October 2008 [ABSTRACT FROM AUTHOR]

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]

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 © 2012 Elsevier Ireland Ltd. All rights reserved.)

Founder mutations, particularly 35delG in the GJB2 gene, have to a large extent contributed to the high frequency of autosomal recessive nonsyndromic hearing loss (ARNSHL). Mutations in transmembrane channel-like gene 1 (TMC1) cause ARNSHL. The p.R34X mutation is the most frequent known mutation in the TMC1 gene. To study the origin of this mutation and determine whether it arose in a common ancestor, we analyzed 21 polymorphic markers spanning the TMC1 gene in 11 unrelated individuals from Algeria, Iran, Iraq, Lebanon, Pakistan, Tunisia, and Turkey who carry this mutation. In nine individuals, we observed significant linkage disequilibrium between p.R34X and five polymorphic markers within a 220 kb interval, suggesting that p.R34X arose from a common founder. We estimated the age of this mutation to be between 1075 and 1900 years, perhaps spreading along the third Hadramaout population movements during the seventh century. A second founder effect was observed in Turkish and Lebanese individuals with markers in a 920 kb interval. Screening for the TMC1 p.R34X mutation is indicated in the genetic evaluation of persons with ARNSHL from North African and Southwest Asia.