First description of novel compound heterozygous mutations in HYCC1: clinical evaluations and molecular analysis in patient with hypomyelinating leukodystrophy-5 with retrospective view.

Hypomyelinating leukodystrophy-5 (HLD5) is a rare autosomal recessive hypomyelination disorder characterized by congenital cataract, progressive neurologic impairment, and myelin deficiency in the central and peripheral nervous system, caused by mutations in the HYCC1 gene. Here we report a 23-year-old girl with HLD5 from unrelated families. Molecular analysis was performed using sequence screening of the HYCC1 gene.

Characterization of a missense variant in COG5 in a Tunisian patient with COG5-CDG syndrome and insights into the effect of non-synonymous variants on COG5 protein.

The clinical diagnosis of patients with multisystem involvement including a pronounced neurologic damage is challenging. High-throughput sequencing methods remains crucial to provide an accurate diagnosis. In this study, we reported a Tunisian patient manifesting hypotonia and global developmental delay with visual and skin abnormalities.

Exploring the role of vitamin D-VDR pathway in pemphigus foliaceous: a novel perspective on disease pathogenesis.

Several auto-immune diseases have been linked to vitamin D deficiency as a contributing environmental factor. Its pleiotropic effects on the immune system, especially its essential role in maintaining immune tolerance, make the vitamin D pathway of great interest. In this study, we focused on Pemphigus foliaceous (PF) in Tunisian population.

Molecular and in silico investigation of a novel ECHS1 gene mutation in a consanguine family with short-chain enoyl-CoA hydratase deficiency and Mt-DNA depletion: effect on trimer assembly and catalytic activity.

Short-chain enoyl-CoA hydratase deficiency (ECHS1D) is a rare congenital metabolic disorder that follows an autosomal recessive inheritance pattern. It is caused by mutations in the ECHS1 gene, which encodes a mitochondrial enzyme involved in the second step of mitochondrial β-oxidation of fatty acids. The main characteristics of the disease are severe developmental delay, regression, seizures, neurodegeneration, high blood lactate, and a brain MRI pattern consistent with Leigh syndrome.

Molecular and computational characterization of ABCB11 and ABCG5 variants in Tunisian patients with neonatal/infantile low-GGT intrahepatic cholestasis: Genetic diagnosis and genotype-phenotype correlation assessment.

Many inherited conditions cause hepatocellular cholestasis in infancy, including progressive familial intrahepatic cholestasis (PFIC), a heterogeneous group of diseases with highly overlapping symptoms. In our study, six unrelated Tunisian infants with PFIC suspicion were the subject of a panel-target sequencing followed by an exhaustive bioinformatic and modeling investigations. Results revealed five disease-causative variants including known ones: (the p.

Characterization of a novel ABCC2 mutation in infantile Dubin Johnson syndrome.

Background And Aims: The Dubin Johnson Syndrome (DJS) occurs mostly in young adults but an early-onset of the disease has been reported in less common forms (Neonatal DJS and Infantile DJS). In this case, the clinical findings are of limit for the DJS diagnosis. Hence, the genetic testing remains the method of choice to provide an accurate diagnosis.

A homozygous ABCB4 mutation causing an LPAC syndrome evolves into cholangiocarcinoma.

Low phospholipid-associated cholelithiasis (LPAC) is characterized by the association of ABCB4 mutations and low biliary phospholipid concentration with symptomatic and recurring cholelithiasis. In the present study, we reported a case of a 63-year-old woman, who presented a biliary pain beginning at the age of 30, recurrent after cholecystectomy, along with "comet-tail shadows" revealed by ultrasonography thus, fulfilling the diagnosis of LPAC. This disease evolved into a cholangiocarcinoma.

Clinical, Molecular, and Computational Analysis Showed a Novel Homozygous Mutation Among the Substrate-Binding Site of ARSA Protein in Consanguineous Family with Late-Infantile MLD.

Metachromatic leukodystrophy (MLD) is a neurodegenerative disorder characterized by progressive demyelination resulting from impaired degradation and thus the accumulation of cerebroside-3-sulfate (sulfatide). It is caused by the deficiency of arylsulfatase A (ARSA) enzyme which is encoded by the ARSA gene. The present study reports the clinical, molecular, and bioinformatic investigation of three patients belonging to a consanguineous family with late-infantile MLD disorder.

Potential dysfunctional effects of synonymous variants: Insights from an exhaustive in silico analysis of the ABCB4 gene.

The multiple drug resistance 3 (MDR3) protein is a canalicular phospholipid translocator involved in the bile secretion and encoded by the ABCB4 gene. Its deficiency is related to a large spectrum of liver diseases. Taking into account the increased evidence about the involvement of synonymous variants in inherited diseases, this study aims to explore the putative effects of silent genetic variants on the ABCB4 expression.

Phenotypic variability in Tunisian PFIC3 patients harboring a complex genotype with a differential clinical outcome of UDCA treatment.

Introduction: Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a chronic autosomal recessive disorder characterized by a wide spectrum of clinical severity generally related to the degree of pathogenicity of the causal sequence variation in ABCB4 gene.

Patients And Methods: The present study reports the molecular investigation by Next Generation Sequencing (NGS) of five related patients with PFIC3 disease followed by bioinformatic analysis. A biochemical follow-up is also performed to assess the response of the ursodeoxycholic acid treatment.

Clinical, Molecular, and Computational Analysis in two cases with mitochondrial encephalomyopathy associated with SUCLG1 mutation in a consanguineous family.

Deficiency of the mitochondrial enzyme succinyl COA ligase (SUCL) is associated with encephalomyopathic mtDNA depletion syndrome and methylmalonic aciduria. This disorder is caused by mutations in both SUCL subunits genes: SUCLG1 (α subnit) and SUCLA2 (β subnit). We report here, two Tunisian patients belonging to a consanguineous family with mitochondrial encephalomyopathy, hearing loss, lactic acidosis, hypotonia, psychomotor retardation and methylmalonic aciduria.

Novel mutations in the CDKL5 gene in complex genotypes associated with West syndrome with variable phenotype: First description of somatic mosaic state.

Introduction: West syndrome is a rare epileptic encephalopathy of early infancy, characterized by epileptic spasms, hypsarrhythmia, and psychomotor retardation beginning in the first year of life.

Methods: The present study reports the clinical, molecular and bioinformatic investigation in the three studied West patients.

Results: The results revealed a complex genotype with more than one mutation in each patient including the known mutations c.

Comparison of in silico prediction and experimental assessment of ABCB4 variants identified in patients with biliary diseases.

Genetic variations of the phosphatidylcholine transporter, ABCB4 cause several biliary diseases. The large number of reported variations makes it difficult to foresee a comprehensive study of each variation. To appreciate the reliability of in silico prediction programs, 1) we confronted them with the assessment in cell models of two ABCB4 variations (E528D and P1161S) identified in patients with low phospholipid-associated cholelithiasis (LPAC); 2) we extended the confrontation to 19 variations that we had previously characterized in cellulo.

In silico investigation of the impact of synonymous variants in ABCB4 gene on mRNA stability/structure, splicing accuracy and codon usage: Potential contribution to PFIC3 disease.

Progressive Familial Intrahepatic Cholestasis type 3 (PFIC3) is an autosomal-recessive liver disease due to mutations in the ABCB4 gene encoding for the MDR3 protein. In the present study, we performed molecular and bioinformatic analyses in PFIC3 patients in order to understand the molecular basis of the disease. The three studied patients with PFIC3 were screened by PCR amplification followed by direct sequencing of the 27 coding exons of ABCB4.