Wafa Cherif

Consanguinity, endogamy, and genetic disorders in Tunisia

Consanguinity refers to marriages between individuals who share at least one common ancestor. In clinical genetics, a consanguineous marriage is defined as a union between two individuals who are related as second cousins or closer, with the inbreeding coefficient (F) equal or higher than 0.0156 (Bittles2001). However, reports on consanguinity rates may sometimes include marriages between third cousins or more distantly related individuals (Hamamy2011). It is estimate that more than 690 million people in the world are consan- guineous (Bittles and Black 2010 ). Middle East, Northern Africa, and South Asia are regions that have historically and culturally had a high rate of consanguineous unions (Al- Awadi et al. 1985; Al-Gazali et al.1997; Jaber et al.1997;Bittles et al.2002; Bener and Alali2006). Recent studieshave shown that 20 % to 50 % of marriages in Arab countries are between relatives (Tadmouri et al. 2009;Bittles2011; Hamamy et al.2011). The rate was 68 % inEgypt (Mokhtar and Abdel-Fattah2001), 51-58 % in Jordan

Genetic homogeneity of mutational spectrum of group-A xeroderma pigmentosum in Tunisian patients

Background  Xeroderma Pigmentosum (XP) is a rare autosomal recessive disorder characterized by cutaneous and ocular alterations. Eight genes, Xeroderma Pigmentosum group A (XPA) to Xeroderma Pigmentosum group G (XPG) and Xeroderma Pigmentosum group V (XPV), are known to be responsible for the disease and products of these genes are involved in the repair of deoxyribonucleic acid (DNA) lesions generated by UV radiation. Several XP patients suffer from neurological defects, found in the XPA (the most common form), D and G groups. The aim of this study was to investigate the mutational spectrum of XPA in Tunisia, in order to propose a simple tool for molecular diagnosis.

Molecular and biochemical characterization of Tunisian patients with glycogen storage disease type III

Glycogen storage disease type III (GSD III) is an autosomal recessive inborn error of metabolism caused by mutations in the glycogen debranching enzyme amylo-1,6-glucosidase gene, which is located on chromosome 1p21.2. GSD III is characterized by the storage of structurally abnormal glycogen, termed limit dextrin, in both skeletal and cardiac muscle and/or liver, with great variability in resultant organ dysfunction. The spectrum of AGL gene mutations in GSD III patients depends on ethnic group. The most prevalent mutations have been reported in the North African Jewish population and in an isolate such as the Faroe Islands. Here, we present the molecular and biochemical analyses of 22 Tunisian GSD III patients. Molecular analysis revealed three novel mutations: nonsense (Tyr1148X) and two deletions (3033_3036del AATT and 3216_3217del GA) and five known mutations: three nonsense (R864X, W1327X and W255X), a missense (R524H) and an acceptor splice-site mutation (IVS32-12A>G). Each mutation is associated to a specific haplotype. This is the first report of screening for mutations of AGL gene in the Tunisian population.

Mutation spectrum of glycogen storage disease type Ia in Tunisia: Implication for molecular diagnosis

SummaryGlycogen storage disease type Ia (GSD Ia; OMIM 232200) is an autosomal recessive disorder of glycogen metabolism caused by a deficiency of the microsomal glucose-6-phosphatase (G6Pase). It is characterized by short stature, hepatomegaly, hypoglycaemia, hyperuricaemia, and lactic acidaemia. Various mutations have been reported in the G6Pase gene (G6PC). In order to determine the mutation spectrum in Tunisia, we performed mutation analysis in 22 Tunisian type I glycogen storage disease (GSD I) patients belonging to 18 unrelated families. All patients were clinically classified as GSD Ia. The R83C mutation was found to be the major cause of GSD Ia, accounting for 24 of 36 mutant alleles (66.6%), The R170Q mutation was the second most frequent mutation; it accounts for 10 of 36 mutant alleles (27.7%). The R83C and R170Q mutations could be rapidly detected by PCR/RFLP. Since the majority of Tunisian patients carried R83C and/or R170Q mutations, we propose direct screening of these mutations as a rapid, valuable and noninvasive tool for diagnosis of GSD Ia in Tunisian as well as in Northern African populations.

Adult gaucher disease in southern Tunisia: report of three cases

BackgroundGaucher disease (GD) is the most frequent lysosomal storage disorder; type 1 is by far the most common form. It is characterized by variability in age of onset, clinical signs and progression. It is usually diagnosed in the first or second decade of life with the appearance of bone pains, splenomegaly and thrombocytopenia, but the disease may be diagnosed at any age between 1 and 73 years. In the present study, we report 3 cases with late onset of GD in whom the disease was a surprise finding including one patient with Parkinson disease. This late onset is described as an adult form of Gaucher disease.FindingsMolecular investigation showed mutational homogeneity in Tunisian adult patients suffering from GD. Indeed, all patients carry the p.N370S mutation: two patients at a homozygous state and one patient at compound heterozygous state.ConclusionThe p.N370S mutation presents a large variability in the onset of the disease and its clinical manifestation supporting the view that GD should be considered as a continuum phenotype rather than a predefined classification.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1701276661617840.

High frequency of W1327X mutation in glycogen storage disease type III patients from central Tunisia

Glycogen storage disease type III (GSD III) is an autosomal recessive disorder caused by the deficiency of glycogen debranching enzyme (AGL). It is characterized by hepatomegaly, progressive myopathy, cardiomyopathy and fasting hypoglycemia. Several mutations in AGL gene have been described in different populations. The W1327X mutation was reported in one Tunisian patient resident in Italy. We looked in this report to determine the frequency of W1327X mutation among Tunisian patients. The W1327X mutation was screening in 26 GSD III patients originated from various geographic locations in Tunisia. The sequence analysis revealed that among nine patients carried the W1327X mutation. Eight of them were from six unrelated families and they were originated from Mahdia (centre of Tunisia) suggesting the existence of a founder effect in this region. Taking into account historical migratory waves, screening for this mutation should be performed in priority for molecular diagnosis confirmation of GSD III in North African populations.

Gaucher disease in Tunisia: High frequency of the most common mutations

a Molecular Investigation of Genetic Orphan Diseases Research Unit, Institut Pasteur de Tunis, Tunisia b Inherited Metabolic Diseases Unit, Pediatric Department, La Rabta Hospital, Tunis, Tunisia c Child Neurological Diseases Unit; Faculty of Medicine, Tunis, Tunisia d Pediatric Department, Sahloul Hospital, Sousse, Tunisia e Neurobiology Genetic Department, Biology Molecular and Cellular Institute, Porto University, Portugal f Metabolic Genetic Laboratory, Medicine Faculty, Cochin, France

Differential impact of consanguineous marriages on autosomal recessive diseases in Tunisia.

Consanguinity is common in Tunisia. However, little information exists on its impact on recessive disorders. In this study, we evaluate the impact of consanguineous marriages on the occurrence of some specific autosomal recessive disorders and consider how other factors, such as population substructure and mutation frequency, may be of equal importance in disease prevalence.

Glycogen storage disease type I in Tunisia: An epidemiological analysis

SummaryObjective: Analysis of epidemiological data concerning GSD I in Tunisia. Subjects and methods: All the cases diagnosed as GSD I between 1992 and 2005 in a paediatric department recruiting all the metabolic diseases referred from the North of Tunisia were reviewed. Individual data (sex, socioeconomic and educational background, geographic origins, insurance coverage) were collected and pedigrees were reconstituted. Results: Twenty-two cases (9 boys and 13 girls from 20 homes) were identified. Fourteen belonged to 11 families originating from the North of Tunisia; ten of them are still alive. Both parents in 4 homes (21%) and one parent in 9 homes (47%) were illiterate. Most of the homes (60%) had a low income and 45% comprised at least 3 children. Only 7 homes (35%) had health insurance. Pedigrees indicated 44 infant deaths and at least 10 other cases fulfilling the clinical features of GSD I but not diagnosed. Conclusion: The paediatric prevalence of GSD I in the North of Tunisia can be estimated to 7.93 cases per one million inhabitants and its incidence to 1/100 000 births. However, it is likely to be more frequent because of underreporting or underdiagnosis leading to precocious deaths.

History of settlement of villages from Central Tunisia by studying families sharing a common founder Glycogenosis type III mutation

Abstract Glycogen storage disease type III (GSD III; Cori disease; Forbes disease) is an autosomal recessive inherited metabolic disorder resulting from deficient glycogen debrancher enzyme activity in liver and muscle. In this study, we focused on a single AGL gene mutation p.W1327X in 16 Tunisian patients from rural area surrounding the region of Mahdia in Central Tunisia. This constitutes the largest pool of patients with this mutation ever described. This study was performed to trace the history of the patients’ ancestries in a single region. After extraction of genomic DNA, exon 31 of AGL gene was sequenced. The patients were investigated for the hypervariable segment 1 of mitochondrial DNA and 17 Y-STR markers. We found that the p.W1327X mutation was a founder mutation in Tunisia Analysis of maternal lineages shows an admixture of autochthonous North African, sub-Saharan and a predominance of Eurasian haplogroups. Heterogeneity of maternal haplogroups indicates an ancient settlement. However, paternal gene flow was highly homogeneous and originates from the Near East. We hypothesize that the p.W1327X mutation was introduced into the Tunisian population probably by a recent migration event; then the mutation was fixed in a small region due to the high rate of consanguineous marriages and genetic drift. The screening for this mutation should be performed in priority for GSD III molecular diagnosis, for patients from the region of Mahdia and those from regions sharing the same settlement history.