Identification of a Novel Mutation in FOXL2 Gene That Leads to Blepharophimosis Ptosis Epicanthus Inversus and Telecanthus Syndrome in a Tunisian Consanguineous Family

International audienceMutations 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

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

Abstract 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.</p

Differential impact of consanguineous marriages on autosomal recessive diseases in Tunisia

International audienceObjectives 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. (c) 2015 Wiley Periodicals, Inc