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Xeroderma pigmentosum (XP, OMIM 278700-278780) is a group of autosomal recessive diseases characterized by hypersensitivity to UV rays. There are seven complementation groups of XP (XPA to XPG) and XPV. Among them, the XP group C (XP-C) is the most prevalent type in Western Europe and in the United States. We report here on the clinical and genetic investigation of XP-C patients in 14 Tunisian families. As the XPC V548A fs X572 mutation has been identified in Algerian and Moroccan populations, Tunisian patients were first screened for this mutation by a direct sequencing of exon 9 of the XPC gene. All patients with a severe clinical form had this mutation, thus showing the homogeneity of the mutational spectrum of XPC in Tunisia. A potential founder effect was searched and confirmed by haplotype analysis. Taking into account the similarity of the genetic background, we propose a direct screening of this mutation as a rapid and cost-effective tool for the diagnosis of XP-C in North Africa.

Fanconi anemia (FA) is a rare autosomal recessive disease characterized by progressive pancytopenia, congenital malformations, and predisposition to acute myeloid leukemia. Fanconi anemia is genetically heterogeneous, with at least eight distinct complementation groups of FA (A, B, C, D1, D2, E, F, and G) having been defined by somatic cell fusion studies. Six genes (FANCA, FANCC, FANCD2, FANCE, FANCG, and FANCF) have been cloned. Mutations of the seventh Fanconi anemia gene, BRCA2, have been shown to lead to FAD1 and probably FAB groups. In order to characterize the molecular defects underlying FA in Tunisia, 39 families were genotyped with microsatellite markers linked to known FA gene. Haplotype analysis and homozygosity mapping assigned 43 patients belonging to 34 families to the FAA group, whereas one family was probably not linked to the FANCA gene or to any known FA genes. For patients belonging to the FAA group, screening for mutations revealed four novel mutations: two small homozygous deletions 1693delT and 1751-1754del, which occurred in exon 17 and exon 19, respectively, and two transitions, viz., 513G fi A in exon 5 and A fi G at position 166 (IV-S24+166A fi G) of intron 24. Two new polymorphisms were also identified in intron 24 (IVS24-5G/A and IVS24-6C/G).

Tunisian population is characterized by its heterogeneous ethnic background and high rate of consanguinity. In consequence, there is an increase in the frequency of recessive genetic disorders including Fanconi anemia (FA). The aim of this study was to confirm the existence of a founder haplotype among FA Tunisian patients and to identify the associated mutation in order to develop a simple tool for FA diagnosis. Seventy-four unrelated families with a total of 95 FA patients were investigated. All available family members were genotyped with four microsatellite markers flanking FANCA gene. Haplotype analysis and homozygosity mapping assigned 83 patients belonging to 62 families to the FA-A group. A common haplotype was shared by 42 patients from 26 families at a homozygous state while five patients from five families were heterozygous. Among them, 85% were from southern Tunisia suggesting a founder effect. Using multiplex ligation-dependent probe amplification (MLPA) technique, we have also demonstrated that this haplotype is associated with a total deletion of exon 15 in FANCA gene. Identification of a founder mutation allowed genetic counseling in relatives of these families, better bone marrow graft donor selection and prenatal diagnosis. This mutation should be investigated in priority for patients originating from North Africa and Middle East.

This study reveals a variation in the excess risk linked to consanguinity according to the type of disorder, suggesting the potential of cryptic population substructure to contribute to disease incidence in populations with complex social structure like Tunisia. It also emphasizes the role of other health and demographic aspects such as mutation frequency and reproductive replacement in diseases etiology.

Xeroderma pigmentosum (XP) is a rare disorder characterized by a high skin sun-sensitivity predisposing to skin cancers at an early age. Among Tunisian XP patients with an intermediate skin phenotype, 92% presented neurological abnormalities related to XPA gene deficiency. Clinical variability of the XP-A phenotype is associated with a mutational heterogeneity. In the present study, two Tunisian families with severe dermatological and neurological XP phenotypes were investigated in order to determine clinical characteristics and genetic basis. Two Tunisian families with four XP affected children were examined in the Dermatology Department. Clinical features showed severe presentation of the disease. Coding regions of the XPA gene were analysed by direct sequencing. Results showed the presence of a novel mutation, p.E111X, in three patients belonging to the same family and presenting a very severe phenotype i.e. development of skin lesions and neurological signs before 1 year age. For the other patient, we identified a nonsense mutation, p.R207X, already identified in a Palestinian XP-A patient. Identification of novel causing mutations in Tunisian XP-A patients shows the genetic and mutational heterogeneity of the disease in Tunisia. Despite a relatively homogenous mutational spectrum, mutational heterogeneity for rare cases is observed because of the high rate of consanguinity.

The XPA R228X mutation is common in Tunisian population. This mutation is associated with a relatively moderate phenotype of the XPA. As all explored patients presented the recurrent mutation XPA R228X, a potential founder effect was searched and confirmed by haplotype analysis. Taking into account similar genetic background, investigation of this mutation should allow a cost effective and rapid diagnosis of XPA in north-African populations.