Impact of missense mutations on the structure-function relationship of human succinyl-CoA synthetase using in silico analysis.

The encephalomyopathic mtDNA depletion syndrome with methylmalonic aciduria is associated with succinyl-CoA synthetase (SCS) deficiency caused by pathogenic variants in genes encoding its two subunits. SCS is a mitochondrial enzyme involved in several metabolic pathways and acts as a heterodimer composed of α and β subunits encoded by SUCLG1 and SUCLA2 genes, respectively. The purpose of this study was to analyze the effects of the most pathogenic non-synonymous single nucleotide polymorphisms (nsSNPs) by applying, using different prediction tools, a filtering strategy, on the 343 and 365 nsSNPs found in SUCLG1 and SUCLA2 genes, respectively, retrieved from the databases, then to evaluate their structural and functional effects using homology modeling and molecular docking.

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.

Mitochondrial genes modulate the phenotypic expression of congenital scoliosis syndrome caused by mutations in the TBXT gene.

Background: Congenital scoliosis (CS) is a spinal disorder caused by genetic-congenital vertebral malformations and may be associated with other congenital defects or may occur alone. It is genetically heterogeneous and numerous genes contributing to this disease have been identified. In addition, CS has a wide range of phenotypic and genotypic variability, which has been explained by the intervention of genetic factors like modifiers and environment genes.

Expanding the genetic and phenotypic spectrum of TRAPPC9 and MID2-related neurodevelopmental disabilities: report of two novel mutations, 3D-modelling, and molecular docking studies.

Intellectual disabilities (ID) and autism spectrum disorders (ASD) have a variety of etiologies, including environmental and genetic factors. Our study reports a psychiatric clinical investigation and a molecular analysis using whole exome sequencing (WES) of two siblings with ID and ASD from a consanguineous family. Bioinformatic prediction and molecular docking analysis were also carried out.

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.

Customized targeted massively parallel sequencing enables the identification of novel pathogenic variants in Tunisian patients with developmental and epileptic encephalopathy.

Objective: To develop a high-throughput sequencing panel for the diagnosis of developmental and epileptic encephalopathy in Tunisia and to clarify the frequency of disease-causing genes in this region.

Methods: We developed a custom panel for next-generation sequencing of the coding sequences of 116 genes in individuals with developmental and epileptic encephalopathy from the Tunisian population. Segregation analyses and in silico studies have been conducted to assess the identified variants' pathogenicity.

Complex genotypes in family with metachromatic leukodystrophy: Effect of trans and cis mutations distribution on the phenotype variability.

Metachromatic leukodystrophy (MLD) is a severe metabolic disorder caused by the deficient activity of arylsulfatase A due to ARSA gene mutations. According to the age of onset, MLD is classified into three forms: infantile, juvenile, and adult. In our study, we aimed to perform a genetic analysis for two siblings with juvenile MLD for a better characterization of the molecular mechanisms behind the disease.

A Novel Mutation in the MAP7D3 Gene in Two Siblings with Severe Intellectual Disability and Autistic Traits: Concurrent Assessment of BDNF Functional Polymorphism, X-Inactivation and Oxidative Stress to Explain Disease Severity.

Intellectual disabilities (ID) and autism spectrum disorders (ASD) are characterized by extreme genetic and phenotypic heterogeneity. However, understanding this heterogeneity is difficult due to the intricate interplay among multiple interconnected genes, epigenetic factors, oxidative stress, and environmental factors. Employing next-generation sequencing (NGS), we revealed the genetic cause of ID and autistic traits in two patients from a consanguineous family followed by segregation analysis.

First report of Tunisian patients with CDKL5-related encephalopathy.

Objective: Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) are associated with a wide spectrum of clinical presentations. Early-onset epileptic encephalopathy (EOEE) is the most recognized phenotype. Here we describe phenotypic features in eight Tunisian patients with CDKL5-related encephalopathy.

A novel homozygous PIGO mutation associated with severe infantile epileptic encephalopathy, profound developmental delay and psychomotor retardation: structural and 3D modelling investigations and genotype-phenotype correlation.

The PIGO gene encodes the GPI-ethanolamine phosphate transferase 3, which is crucial for the final synthetic step of the glycosylphosphatidylinositol-anchor serving to attach various proteins to their cell surface. These proteins are intrinsic for normal neuronal and embryonic development. In the current research work, a clinical investigation was conducted on a patient from a consanguineous family suffering from epileptic encephalopathy, characterized by severe seizures, developmental delay, hypotonia, ataxia and hyperphosphatasia.

Vitamin B1 deficiency leads to high oxidative stress and mtDNA depletion caused by SLC19A3 mutation in consanguineous family with Leigh syndrome.

Leigh syndrome (LS) and Leigh-like spectrum are the most common infantile mitochondrial disorders characterized by heterogeneous neurologic and metabolic manifestations. Pathogenic variants in SLC carriers are frequently reported in LS given their important role in transporting various solutes across the blood-brain barrier. SLC19A3 (THTR2) is one of these carriers transporting vitamin-B1 (vitB1, thiamine) into the cell.

Mutation in the β-tubulin gene TUBB4A results in epileptic encephalopathy associated with hypomyelinated leucodystrophy: Unexpected findings reveal genetic mosaicism.

Introduction: Epileptic encephalopathies (EEs) are a group of heterogeneous epileptic syndromes characterized by early-onset refractory seizures, specific EEG abnormalities, developmental delay or regression and intellectual disability. The genetic spectrum of EE is very wide with mutations in a number of genes having various functions, such as those encoding AMPA ionotropic and glutamate receptors as well as voltage-gated ion channels. However, the list of EE-responsible genes could certainly be enlarged by next-generation sequencing.

First description of the MEGDEHL syndrome in the Tunisian population via whole-exome sequencing: Novel nonsense mutation in SERAC1 gene.

Introduction: MEGDEL syndrome is a rare recessive disorder, with about 100 cases reported worldwide, which is defined by 3-methylglutaconic aciduria (MEG), deafness (D), encephalopathy (E) and Leigh-like syndrome (L). When these manifestations were added to hepatopathy (H), the syndrome was labelled as MEGD(H)EL. Mutations in SERAC1 gene encoding a serine active site containing 1 protein were described in patients affected by this syndrome.

A novel thymidine phosphorylase mutation in a family with Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE): Molecular docking, dynamic simulation and computational investigations.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE; OMIM 603041) is a rare inherited metabolic disorder mostly caused by mutations in TYMP gene encoding thymidine phosphorylase (TP) protein that affects the mitochondrial nucleotide metabolism. TP, functionally active as a homodimer, is involved in the salvage pathway of pyrimidine nucleosides. MNGIE-like syndrome having an overlapping phenotype of MNGIE was also described and has been associated with mutations in POLG and RRM2B genes.

Identification of a novel homozygous mutation in NAXE gene associated with early-onset progressive encephalopathy by whole-exome sequencing: in silico protein structure characterization, molecular docking, and dynamic simulation.

Progressive encephalopathy with brain edema and/or leukoencephalopathy, PEBEL1, is a severe neurometabolic disorder characterized by rapidly progressive neurologic deterioration associated with a febrile illness. PEBEL1 is a lethal encephalopathy caused by NAXE gene mutations. Here we report a 6-month-old boy with mitochondrial encephalomyopathy from a consanguineous family.

Pustular psoriasis of pregnancy: Clinical and genetic characteristics in a series of eight patients and review of the literature.

Pustular psoriasis of pregnancy (PPP) can lead to life-threatening complications. The objective of this study is to report clinical and genetic spectrum, prognostic factors and management options. A retrospective study was designed including eight PPP patients.

Clinical and genetic investigation of ichthyosis in familial and sporadic cases in south of Tunisia: genotype-phenotype correlation.

Background: Ichthyosis is a heterogeneous group of Mendelian cornification disorders that includes syndromic and non-syndromic forms. Autosomal Recessive Congenital Ichthyosis (ARCI) and Ichthyosis Linearis Circumflexa (ILC) belong to non-syndromic forms. Syndromic ichthyosis is rather a large group of heterogeneous diseases.

A large consanguineous family with a homozygous Metabotropic Glutamate Receptor 7 (mGlu7) variant and developmental epileptic encephalopathy: Effect on protein structure and ligand affinity.

Background: Developmental and epileptic encephalopathies (DEE) are chronic neurological conditions where epileptic activity contributes to the progressive disruption of brain function, frequently leading to impaired motor, cognitive and sensory development.

Patients And Methods: The present study reports a clinical investigation and a molecular analysis by Next Generation Sequencing (NGS) of a large consanguineous family comprising several cases of developmental and epileptic encephalopathy. Bioinformatic prediction and molecular docking analysis were also carried out.

Mitochondrial disease patients with novel ND4 12058A > C and ND1 m.3911A > G variations: implications for a role in the phenotype following a bioinformatic investigation.

Mitochondrial diseases include a wide group of clinically heterogeneous disorders caused by a dysfunction of the mitochondrial respiratory chain and can be related to mutations in nuclear or mitochondrial DNA genes. In the present report, we performed a whole mitochondrial genome screening in two patients with clinical features of mitochondrial diseases. Mutational analysis revealed the presence of two undescribed heteroplasmic mitochondrial variations, the m.

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 first description of ataxia with vitamin E deficiency associated with MT-TG gene mutation.

Ataxia with isolated vitamin E deficiency (AVED) is a rare autosomal recessive cerebellar ataxia disorder that is caused by a mutation in the alpha-tocopherol transfer protein gene TTPA, leading to a lower level of serum vitamin E. Although it is almost clinically similar to Friedreich's ataxia, its devastating neurological features can be prevented with appropriate treatment. In this study, we present a patient who was initially diagnosed with Friedreich's ataxia, but was later found to have AVED.

Unusual double mutation in MECP2 and CDKL5 genes in Rett-like syndrome: Correlation with phenotype and genes expression.

Introduction: Rett syndrome (RTT) is a neuro-developmental disorder affecting almost exclusively females and it divided into classical and atypical forms of the disease. RTT-like syndrome was also described and presents an overlapping phenotype of RTT. RTT-like syndrome has been associated with several genes including MECP2 and CDKL5 having common biological pathways and regulatory interactions especially during neural maturation and synaptogenesis.