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

OBJECTIVES: 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. METHODS: Consanguinity profiles were retrospectively studied among 425 Tunisian patients suffering from autosomal recessive xeroderma pigmentosum, dystrophic epidermolysis bullosa, nonsyndromic retinitis pigmentosa, Gaucher disease, Fanconi anemia, glycogenosis type I, and ichthyosis, and compared to those of a healthy control sample. RESULTS: Consanguinity was observed in 341 cases (64.94%). Consanguinity rates per disease were 75.63, 63.64, 60.64, 61.29, 57.89, 73.33, and 51.28%, respectively. First-cousin marriages were the most common form of consanguinity (48.94%) with the percentages of 55.46, 45.46, 47.87, 48.39, 45.61, 56.66, and 35.90%, respectively. A very high level of geographic endogamy was also observed (93.92%), with the values by disease ranging between 75.86 and 96.64%. We observed an overall excess risk associated to consanguinity of nearly sevenfold which was proportional to the number of affected siblings and the frequency of disease allele in the family. Consanguinity was significantly associated with the first five cited diseases (odds ratio = 24.41, 15.17, 7.5, 5.53, and 5.07, respectively). However, no meaningful effects were reported among the remaining diseases. CONCLUSIONS: 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.

[Molecular exploration of the R91W (RPE65 gene) in Tunisian patients with early onset retinal dystrophy and early onset retinitis pigmentosa]. / Exploration moléculaire de la R91W (gene RPE65) chez des patients Tunisiens atteints de "Early Onset Retinal Dystrophy" et de la rétinopathie pigmentaire à age de début précoce.

BACKGROUND: Inherited retinal dystrophies are the major causes of blindness and visual impairment. Visual loss is due to neurosensory retinal and pigment epithelium cells degeneration. The most severe were Leber Congenital amaurosis (LCA), juvenile retinitis pigmentosa (RP) and early onset RP. The LCA and juvenile RP are called «Early Onset Retinal Dystrophy¼ (EORD). OBJECTIVE: Molecular exploration of the R91W (RPE65 gene) in Tunisian patients with Early Onset Retinal Dystrophy and early onset RP. METHODS: All patients underwent a complete ophthalmological and a general examinations. The R91W exploration was performed by direct sequencing of exon 4 of the RPE65 gene and enzyme digestion. RESULTS: Among 47 patients, 13 were from Nabeul. Twenty three had an EROD with a visual loss under the age of 2 years. Twenty four were with early onset RP and had these symptoms between the ages of 4 and 10 years. The best corrected visual acuity ranged from 2/10 to 1/60. Among the explored 94 chromosomes, the R91W (325C>T) allele was identified in heterozygous state in a sibling from Nabeul. The allele frequency was 2.12% (2/94). CONCLUSION: All our patients had severe forms of RP with a decrease in visual acuity and a wide advanced retinal degeneration. The R91W mutation (325C>T) was not the major cause of EORD and early onset RP among Tunisian patients.

[Clinical characterization of the Stargardt disease and molecular exploration of the c.2041C>T mutation (ABCA4 gene) in Tunisian patients]. / Caractérisation clinique de la maladie de Stargardt et exploration moléculaire de la c.2041C>T (gène ABCA4) chez des patients tunisiens.

In order to charaterize the Stargardt disease, the molecular exploration of the c.2041C>T mutation (ABCA4 gene) and genotype phenotype correlation in Tunisian patients, seven unrelated propositi underwent a complete ophthalmological examination. The search for the mutation was performed by a direct sequencing after a specific amplification of exon 14 of the ABCA4 gene. Baseline, the average age of propositi was 20.7 ± 15 years and the sex-ratio was 1.3. The age of the visual impairment perception was 8.1 ± 3.2 years. In all patients, the loss of visual acuity was bilateral and ranged from "counting fingers" to 3.2/10. Fundus and retinal fluorescein angiography examination showed advanced stages of the disease. The allele frequency of the c.2041C>T was 28.5% (4/14). We have reported this mutation in two patients. Their average age at onset was 5 and a half years and the disease progression was rapid with a severe visual loss after 1 and 5 years. All patients had a juvenile macular dystrophy with flavimaculatus flecks. To our knowledge, we reported for the first time the homozygous state of the c.2041C>T mutation. Among homozygous patients, the age at onset was early, the loss of visual acuity was important and the prognosis was severe. Due to the severity of the phenotype and the high rate of inbreeding, genetic counseling for healthy heterozygotes is essential.

Coexistence of mal de Meleda and congenital cataract in a consanguineous Tunisian family: two case reports.

INTRODUCTION: Mal de Meleda is a rare form of palmoplantar keratoderma, with autosomal recessive transmission. It is characterized by diffuse erythema and hyperkeratosis of the palms and soles. Recently, mutations in the ARS (component B) gene (ARS, MIM: 606119) on chromosome 8q24.3 have been identified in families with this disorder. Congenital cataract is a visual disease that may interfere with sharp imaging of the retina. Mutations in the heat-shock transcription factor 4 gene (HSF4; MIM: 602438) may result in both autosomal dominant and autosomal recessive congenital cataracts. CASE PRESENTATION: A Tunisian family with two female siblings aged 45 and 30 years, presented with a clinical association of mal de Meleda and congenital cataract. The two patients exhibited diffuse palmoplantar keratodermas. One of them presented with a total posterior subcapsular cataract and had a best corrected visual acuity at 1/20 in the left eye and with the right eye was only able to count fingers at a distance of one foot. The other woman had a slight posterior subcapsular lenticular opacity and her best corrected visual acuity was 8/10 in the right eye and with her left eye she was only able to count fingers at a distance of one foot. A mutational analysis of their ARS gene revealed the presence of the homozygous missense mutation C99Y and two single nucleotide polymorphisms (-55G>C and -60G>C). The splice mutation (c.1327+4A-G) within intron 12 of the HSF4 gene, which has been previously described in Tunisian families with congenital cataract, was not found in the two probands within this family. CONCLUSION: To the best of our knowledge, such original clinical association has not been reported previously. The association of these two autosomal recessive diseases might have occurred in this family due to a high degree of inbreeding. The C99Y mutation may be specific to the Tunisian population as it has been exclusively reported so far in only three Tunisian families with mal de Meleda.

Identification of a novel mutation in FOXL2 gene that leads to blepharophimosis ptosis epicanthus inversus and telecanthus syndrome in a Tunisian consanguineous family.

Mutations in FOXL2 gene are responsible for blepharophimosis ptosis epicanthus inversus and telecanthus syndrome (BPES). The BPES syndrome is a rare autosomal dominant genetic disease characterized by eyelid malformations associated with premature ovarian failure (BPES type I) or not (BPES type II). The human FOXL2 protein (376 aa) contains a 100 amino-acid DNA-binding forkhead domain (residues 52-152) and a polyalanine tract (residues 221-234). In the present study, we report the molecular investigation of four affected members with BPES syndrome in a Tunisian consanguineous family. To identify the causative mutation, we performed a direct sequencing of the FOXL2 gene. The sequence analysis of the coding exon revealed a novel frameshift mutation g.1113 dup C, c.876 dup C, p.P292 Fs. The mutation is located downstream of the polyalanine tract and causes the protein extension to 532 aa. This study reports for the first time a novel frameshift mutation in two-generation consanguineous Tunisian family with BPES. Our results expand the spectrum of FOXL2 mutations.

Central areolar choroidal dystrophy associated with inherited drusen in a multigeneration Tunisian family: exclusion of the PRPH2 gene and the 17p13 locus.

Central areolar choroidal dystrophy (CACD) is a rare inherited disease, which causes progressive profound loss of vision in patients during their fourth decade. It is characterized by atrophy of retinal pigment epithelium, photoreceptors and choriocapillaris. The disease showed a genetic heterogeneity. Previously, mutations in the peripherin/RDS gene and a linkage to the CACD locus in the 17p13 region have been reported in CACD families. In this study, we report on a clinical and genetic investigation of CACD in a large Tunisian consanguineous family with 21 affected individuals in three living generations. CACD has been associated with drusen in some of them. Linkage analysis and mutational screening exclude linkage to the PRPH2/RDS gene and to the CACD locus. These data provide further evidence of the genetic heterogeneity of CACD.