Farah Ouechtati

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

IntroductionMal 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 presentationA 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.ConclusionTo 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.

Clinical and genetic investigation of a large Tunisian family with complete achromatopsia: identification of a new nonsense mutation in GNAT2 gene

Complete achromatopsia is a rare autosomal recessive disease associated with CNGA3, CNGB3, GNAT2 and PDE6C mutations. This retinal disorder is characterized by complete loss of color discrimination due to the absence or alteration of the cones function. The purpose of the present study was the clinical and the genetic characterization of achromatopsia in a large consanguineous Tunisian family. Ophthalmic evaluation included a full clinical examination, color vision testing and electroretinography. Linkage analysis using microsatellite markers flanking CNGA3, CNGB3, GNAT2 and PDE6C genes was performed. Mutations were screened by direct sequencing. A total of 12 individuals were diagnosed with congenital complete achromatopsia. They are members of six nuclear consanguineous families belonging to the same large consanguineous family. Linkage analysis revealed linkage to GNAT2. Mutational screening of GNAT2 revealed three intronic variations c.119−69G>C, c.161+66A>T and c.875−31G>C that co-segregated with a novel mutation p.R313X. An identical GNAT2 haplotype segregating with this mutation was identified, indicating a founder mutation. All patients were homozygous for the p.R313X mutation. This is the first report of the clinical and genetic investigation of complete achromatopsia in North Africa and the largest family with recessive achromatopsia involving GNAT2; thus, providing a unique opportunity for genotype–phenotype correlation for this extremely rare condition.

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.

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.

Clinical and genetic investigation of isolated microspherophakia in a consanguineous Tunisian family

Microspherophakia seems to be the most specific feature of the Weill–Marchesani Syndrome, which could be due to mutations within the ADAMTS10 gene. As the locus responsible for isolated microspherophakia is still unknown, because the reported cases are rare, we checked whether the ADAMTS10 gene is involved in isolated microspherophakia in a Tunisian family. A consanguineous family (MSP-M), including six family members and two patients, presented with decreased vision secondary to bilateral isolated microspherophakia. A linkage analysis was carried out using microsatellite markers flanking the ADAMTS10 candidate gene. In the MSP-M family, isolated microspherophakia is likely inherited as an autosomal-recessive disease. Using a homozygosity-mapping strategy, haplotypic analysis using four STRs showed an exclusion of linkage between the ADAMTS10 gene and the disease locus in this family. Our study suggests that isolated microspherophakia and the Weill–Marchesani Syndrome are not allelic to the ADAMTS10 gene.

Clinical and Genetic Investigation of Atrial Septal Defect with Atrioventricular Conduction Defect in a Large Consanguineous Tunisian Family

BACKGROUND Atrial septal defect (ASD) is an autosomal dominant disease characterized by left-to-right shunting and increased right ventricular output. Approximately 5-10% of congenital heart diseases (CHD) are due to ASD, which is one of the most frequent CHD found in adults. The gene responsible for ASD was mapped to chromosome 5q35 encoding the transcription factor NKX2-5 that plays an important role for the regulation of septation during cardiac morphogenesis. METHODS A Tunisian family including four affected members was investigated. Individuals were genotyped using the polymorphic microsatellite markers D5S394 and D5S2069 overlapping the NKX2-5 gene. RESULTS We report here clinical and molecular investigation of a Tunisian consanguineous family with four affected members. Two presented with ASD associated with prolonged PR interval, whereas the other two presented only a prolonged PR interval. We also identified five asymptomatic individuals in the same family with ventricular preexcitation. Although the patients were products of a consanguineous marriage, no other abnormalities were observed in this family. Genotyping and linkage analysis showed exclusion of linkage between the gene responsible for ASD in this family and NKX2.5 gene. CONCLUSIONS Our results further confirm the genetic heterogeneity of ASD.

515 Formes familiales de rétinopathie pigmentaire, étude clinique et génétique

Introduction La retinopathie pigmentaire (RP) est caracterisee par sa triple heterogeneite : clinique, genetique et moleculaire. Le but du travail est de degager les principales caracteristiques cliniques et genetiques des RP. Materiels et Methodes Il s’agit d’une retrospective portant sur 36 patients issus de 9 familles originaires de la region du Cap-Bon (Tunisie), atteinte des RP non syndromique. Tous nos patients ont beneficie d’un examen ophtalmologique et general complete par des explorations para-cliniques et d’une etude genetique. Discussion Nos resultats cliniques ont revele une grande heterogeneite. En effet, trois formes cliniques en fonction de l’âge de debut ont ete retrouvees : la RP de la premiere enfance, la RP a debut precoce et la RP classique. Trois formes cliniques en fonction des donnees du FO ont egalement ete identifiees : RP a spicules, retinopathie ponctuee albescente et RP avec mottes pigmentaires. Les complications a type de cataracte et d’œdeme maculaire cystoide etaient presentes, dans respectivement 52 % et 11 % des cas. L’analyse des arbres genealogiques a conclu a un mode de transmission autosomique recessif dans 8 familles et autosomique dominant dans une famille. L’etude moleculaire (analyse de liaison genetique et sequencage de l’ADN) a mis en evidence la mutation R91W sur le gene RPE65 chez tous les individus atteints appartenant a deux familles avec phenotype de RP de la premiere enfance et avec au FO des mottes pigmentaires, suggerant ainsi une correlation phenotype-genotype. Les genes RHO, RDS, ABCA4 et ROM1 ont ete exclus. Conclusion Dans la majorite des RP, on ne retrouve pas de correlation phenotypegenotype evidente, ce qui ne facilite pas la caracterisation du defaut moleculaire responsable de ces pathologies. Toutefois, devant tout patient atteint de RP et rapportant une histoire familiale d’hesperanopie, une enquete genetique et moleculaire s’impose en vue de therapie future.

689 Hétérogénéité clinique et mutationnelle chez une grande famille consanguine Stargardt-like

Introduction La maladie de Stargardt est la plus frequente des heredo-degenerescences maculaires et peut se manifester sous differentes formes cliniques. Il s’agit le plus souvent d’une transmission autosomique recessive par mutation du gene ABCA4 qui code pour une proteine ABCR. Nous rapportons le cas d’une famille tunisienne consanguine dont certains membres presentent des phenotypes Stargardt-like differents. L’atteinte semble etre transmise sur le mode autosomique recessif. Une analyse genetique a ete realisee a la recherche d’une eventuelle correlation genotype-phenotype. Materiels et Methodes Cette etude a concerne deux familles nucleaires consanguines chez lesquelles nous avons retrouve sept sujets atteints. Tous les membres ont beneficie d’un examen ophtalmologique : acuite visuelle, champ visuel, fond d’œil, angiographie retinienne a la fluoresceine et electroretinogramme. Un genotypage a ete realise utilisant les microsatellites D1S2813 et D1S2849 pour le gene ABCA4 et un autre marqueur intragenique. Une recherche des mutations deja connues a ete realisee par micropuce du gene ABCA4 pour un patient et par sequencage ciblant huit exons pour les autres. Resultats Sur le plan clinique, trois phenotypes differents ont ete individualises : un phenotype de Stargardt avec maculopathie et silence choroidien pour une patiente, un phenotype de Stargardt-fundus flavimaculatus pour quatre patients et un phenotype pouvant correspondre a un Stargardt evolue ou a une cone rod dystrophy avec une atrophie generalisee de la retine pour deux patients. L’analyse genetique a demontre l’implication d’une mutation du gene ABCA4 dans l’apparition de la maladie et il existe chez les patients atteints trois individus recombinants. La mutation Arg 681Ter a ete retrouvee a l’etat heterozygote dans une des branches familiales. Aucune des mutations connues du gene n’a ete retrouvee chez les autres membres atteints de la famille. Discussion Ceci suggere la presence de mutations genetiques differentes au niveau du gene ABCA4. Conclusion Dans le present travail, nous rapportons une large genealogie presentant une dystrophie retinienne liee au gene ABCA4. Bien que cette famille soit fortement consanguine et qu’une seule entite genetique semble etre impliquee, elle presente une forte heterogeneite phenotypique due probablement a une heterogeneite mutationnelle.