Novel RAB3GAP1 Mutation in the First Tunisian Family With Warburg Micro Syndrome

Background@#and Purpose Warburg Micro syndrome (WARBM) is a rare autosomal recessive genetic disease characterized by ocular, neurologic, and endocrine anomalies. WARBM is a phenotypically and genetically heterogeneous syndrome caused by mutations in RAB3GAP1, RAB3GAP2, RAB18, and TBC1D20. Here we present the clinical and genetic characterization of a consanguineous Tunisian family with a WARBM phenotype presenting two pathogenic variations, one of which is on RAB3GAP1. @*Methods@#We applied whole-exome sequencing (WES) to two affected young males presenting a WARBM-compatible phenotype. @*Results@#We reveal a new variation in RAB3GAP1 (NM_012233.3: c.297del, p.Gln99fs) and another variation in ABCD1 (NM_000033: c.896A>G, p.His299Arg). Each of these mutations, which in silico predictions concluded as being pathogenic variations, affects a critical protein region. Both affected males presented a WARBM-compatible phenotype, with severe intellectual disability, severe developmental delay, postnatal growth delay, postnatal microcephaly, congenital bilateral cataracts, general hypotonia, and a thin corpus callosum without a splenium. However, intrafamilial clinical heterogeneity was present, since only the oldest child had large ears, microphthalmia, foot deformities, and a genital anomaly, and only the youngest child had microcornea. Despite the mutation identified in ABCD1, our patients did not have any Xlinked symptoms of adrenoleukodystrophy disorder that are usually caused by ABCD1 mutations, which prompted our interest in clinical monitoring. @*Conclusions@#WES analysis of a consanguineous Tunisian family with WARBM revealed a novel variation in RAB3GAP1 (NM_012233.3: c.297del, p.Gln99fs) that is most likely pathogenic and allowed us to confirm the diagnosis of WARBM.

Non-syndromic autosomal recessive mental retardation in Tunisian families: exclusion of GRIK2 and TUSC3 genes

Mental retardation is one of the most frequent major handicap, with a 1-3% frequency in the general population, it appear a major problem of public health. The recent progress of molecular biology and cytogenetic allowed to identify new genes for non syndromic autosomal recessive mental retardation [NSAR-MR]. Genetic analysis of NSAR-MR: the GRIK2 gene [6q16.3-q21] and the TUSC3 gene [8p22]. Four Tunisian families with NSAR-MR were included in this study. Genotyping was made using polymorphic microsatellite markers and statistical analysis was validated using the Fast Link programme of the Easy linkage software [V4:00beta]. Genotyping and linkage analysis excluded linkage of the GRIK2 gene and TUSC3 gene. Our results confirm the extreme genetic heterogeneity of NSAR-MR

[Treacher collins syndrome: clinical and genetic aspects about 4 cases]

Treacher Collins syndrome was first mentioned by Thompson in 1847, and described by Treacher Collins in 1900, then it was called mandibulo-facial dysostosis and well defined by Franceschetti in 1949. It is a very rare affection occurring 1 in 50.000 live births, which includes facial and auricular anomalies leading to functional, morphological and psychological difficulties due to related handicaps. Treacher Collins syndrome is inherited as autosomal dominant pattern with a variable expressivity and incomplete penetrance of "TCOF1" gene localized at incomplete penetrance of "TCOF1" gene localized at 5q31.3q32. Today the gene is well identified and several mutations have been reported. In this paper we report the case of 4 Tunisian unrelated girls with Treacher Collins syndrome. One of them was born from an affected father. Clinical diagnostic was performed between age 12 days and 2 years demonstrating the large dysmorphic expression. Main clinical features were present in all reported cases. Family at risk might have genetic counselling and probably prenatal diagnostic in some situations. Out of our observations, we gave genetic counselling and proposed ultrasound prenatal diagnosis for two families without molecular study

[Molecular analysis of the smni and naip genes in 60 Tunisian spinal muscular atrophy patients]

In this study we examined the deletion of SMN and NAIP genes in 60 Tunisian families There were 35 patients with type I SMA. 18 with type II SMA, 6 with type Ill SMA and 1 with type IV SMA .The age of onset was before 6 months for type I, between 6 months and 2 years for type II. between 2 years and 17 years for type III and 30 years for type IV. Exon 7 of SMN 1 gene was homozygously deleted in 95% [57/60] of SMA patients. There was a higher frequency of homozygous absence of SMN I in type I and type 11 [100% and 94% respectively] than in type III [66,7%]. SMN 1 exon 8 was undetectable in 88%[53/60] of patients .The case type II patient with homozygous deletion of SMN I exon 7 and not exon 8 was tested for the presence of a hybrid SMN gene. This patient showed in the second PCR a SMN I exon 8 product by restriction site assay indicating that a gene conversion event had occurred. All parents' individuals retained one copy of their SMN I gene. Exon 5 of NAIP gene was homozygously deleted in 58% [35/60] of patients [77% in type I [27/35], 27, 7% in type 11 [5/18], 50% [3/6] in type III [Table 1]. No patient had a deletion in NAIP gene without a deletion in the SMN1 gene. Homozygous deletion of NAIP exon 5 was detected in 1 parent. Our results show that the incidence of NAIP deletion is higher in the more severe SMA cases