Novel splice variants implicated in inherited retinal dystrophies in two Moroccan families.

Background: Inherited retinal dystrophies (IRD) are a group of conditions resulting in visual impairments or blindness, due to the dysfunction of the retina. It affects 1/2000 individuals worldwide, and over 324 genes and 20 phenotypes are implicated in these pathologies. The most common form of IRD is Retinitis Pigmentosa, followed by Stargardt diseases, Leber congenital amaurosis and cone/cone-rod dystrophies.

JAK2 mutational status and the contribution of TERT and JAK2 polymorphisms to the occurrence of myeloproliferative neoplasms in Eastern Morocco.

Background: The JAK2 V617F somatic mutation is a hallmark of myeloproliferative neoplasms (MPN) and is present in some patients with splanchnic venous thrombosis (SVT).

Objectives: We investigated for the first time in Eastern Morocco the JAK2 mutational status and germline risk factors, such as the TERT and JAK2 polymorphisms, in MPN and SVT patients.

Methods: This study included 38 patients with MPN, 24 patients presenting with SVT and 60 healthy donors from the BRO Biobank.

Biallelic variants lead to a neurodevelopmental phenotype with gradual neurological impairment.

Biallelic variants in NADH (nicotinamide adenine dinucleotide (NAD) + hydrogen (H))-ubiquinone oxidoreductase 1 alpha subcomplex 13 have been linked to mitochondrial complex I deficiency, nuclear type 28, based on three affected individuals from two families. With only two families reported, the clinical and molecular spectrum of NADH-ubiquinone oxidoreductase 1 alpha subcomplex 13related diseases remains unclear. We report 10 additional affected individuals from nine independent families, identifying four missense variants (including recurrent c.

Clinical and Molecular Spectrum of Wilson Disease in the Arab World: A Systematic Review.

Wilson disease is a rare monogenic disease characterized by copper overload in various organs, mainly the liver, the brain and the eyes. It has a prevalence ranging between 1/30,000 and 1/50,000, and it is caused by pathogenic variants in the ATP7B gene, which encodes a copper-transporting ATPase essential for regulating liver copper levels by directing copper to the secretory pathway and exporting excess copper into bile. It is a fatal disease if left untreated; however early diagnosis and effective treatment enable patient's outcome improvement.

Two Cases of ROSAH-Like Syndrome Restricted to the Ophthalmologic Presentation.

Purpose: To report the clinical presentation and follow-up, including the optical coherence tomography, angiography and electrophysiology of two individuals from the same family presenting with an isolated retinal dystrophy and optic nerve edema who were diagnosed with ROSAH-like syndrome.

Method: Observational case report of a 55-year-old woman and her 36-year-old son with a genetic analysis of ROSAH, after a long-term follow-up.

Results: Both the mother and her son displayed severe optic nerve infiltration and retinal pigment atrophy with intraocular inflammation, which were not improved by immunosuppressive treatment.

Carrier frequency and molecular basis of hemoglobinopathies among blood donors in eastern Morocco: Implications for blood donation and genetic diagnosis.

Background: Hemoglobinopathies represent the most commonly inherited autosomal recessive blood disorders in the world. The aim of this study was to determine the carrier frequency and molecular basis of hemoglobinopathies among blood donors in eastern Morocco. This is the first study of its kind for this country.

Triple-A Syndrome in Morocco: Founder Effect, Age Estimation of the c.1331+1G>A Variant, and Implications for Genetic Diagnosis.

Introduction: Triple-A syndrome (Triple-A) is an autosomal recessive disorder characterized by alacrimia, achalasia, and adrenal insufficiency. Several variants on the gene have been described, and some variants are clustered in particular geographical areas, such as the c.1331+1G>A variant which is very frequent in North Africa.

The human OPA1 mutation induces adult onset and progressive auditory neuropathy in mice.

Dominant optic atrophy (DOA) is one of the most prevalent forms of hereditary optic neuropathies and is mainly caused by heterozygous variants in OPA1, encoding a mitochondrial dynamin-related large GTPase. The clinical spectrum of DOA has been extended to a wide variety of syndromic presentations, called DOAplus, including deafness as the main secondary symptom associated to vision impairment. To date, the pathophysiological mechanisms underlying the deafness in DOA remain unknown.

Expanding the genetic spectrum of mitochondrial diseases in Tunisia: novel variants revealed by whole-exome sequencing.

Inherited mitochondrial diseases are the most common group of metabolic disorders caused by a defect in oxidative phosphorylation. They are characterized by a wide clinical and genetic spectrum and can manifest at any age. In this study, we established novel phenotype-genotype correlations between the clinical and molecular features of a cohort of Tunisian patients with mitochondrial diseases.

Homozygous Missense Variants in FOXI1 and TMPRSS3 Genes Associated with Non-syndromic Deafness in Moroccan Families.

One of the most prevalent sensorineural disorders, autosomal recessive non-syndromic hearing loss (ARNSHL) which can affect all age groups, from the newborn (congenital) to the elderly (presbycusis). Important etiologic, phenotypic, and genotypic factors can cause deafness. So far, the high genetic variability that explains deafness makes molecular diagnosis challenging.

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.

A novel variant in BMPR1B causes acromesomelic dysplasia Grebe type in a consanguineous Moroccan family: Expanding the phenotypic and mutational spectrum of acromesomelic dysplasias.

Acromesomelic dysplasia Grebe type (AMD Grebe type) is an autosomal recessive trait characterized by short stature, shortened limbs and malformations of the hands and feet. It is caused by variants in the growth differentiation factor 5 (GDF5) or, in rare cases, its receptor, the bone morphogenetic protein receptor-1B (BMPR1B). Here, we report a novel homozygous BMPR1B variant causing AMD Grebe type in a consanguineous Moroccan family with two affected sibs from BRO Biobank.

Genotype-phenotype correlations in RHOBTB2-associated neurodevelopmental disorders.

Purpose: Missense variants clustering in the BTB domain region of RHOBTB2 cause a developmental and epileptic encephalopathy with early-onset seizures and severe intellectual disability.

Methods: By international collaboration, we assembled individuals with pathogenic RHOBTB2 variants and a variable spectrum of neurodevelopmental disorders. By western blotting, we investigated the consequences of missense variants in vitro.

Autosomal recessive Leber hereditary optic neuropathy, a new neuro-ophthalmo-genetic paradigm.

Leber hereditary optic neuropathy (LHON) is a primary inherited neurodegenerative disorder of the optic nerve. It has been ascribed to variants in the mitochondrial genome, mainly the m.3460G>A, m.

The top 10 most frequently involved genes in hereditary optic neuropathies in 2186 probands.

Hereditary optic neuropathies are caused by the degeneration of retinal ganglion cells whose axons form the optic nerves, with a consistent genetic heterogeneity. As part of our diagnostic activity, we retrospectively evaluated the combination of Leber hereditary optic neuropathy mutations testing with the exon sequencing of 87 nuclear genes on 2186 patients referred for suspected hereditary optic neuropathies. The positive diagnosis rate in individuals referred for Leber hereditary optic neuropathy testing was 18% (199/1126 index cases), with 92% (184/199) carrying one of the three main pathogenic variants of mitochondrial DNA (m.

First characterization of LTBP3 variants in two Moroccan families with hypoplastic amelogenesis imperfecta.

Objectives: To decipher and improve the molecular diagnosis of Hypoplastic Amelogenesis Imperfecta in Morocco.

Design: Using whole exome sequencing, we analyzed two Moroccan families with Hypoplastic Amelogenesis Imperfecta. The 2 patients from the first family had dental anomalies and short stature syndrome, brachyolmia and nephrocalcinosis with difference in severity, while the proband of the second family had Hypoplastic Amelogenesis Imperfecta with a suspicion of brachyolmia.

Next-Generation Sequencing Identifies Novel Variants in Patients with Late-Onset Dominant Optic Atrophy.

Dominant Optic Atrophy (DOA) is one of the most common inherited mitochondrial diseases, leading to blindness. It is caused by the chronic degeneration of the retinal ganglion cells (RGCs) and their axons forming the optic nerve. Until now, DOA has been mainly associated with genes encoding proteins involved in mitochondrial network dynamics.

Molecular heterogeneity of β-thalassemia variants in the Eastern region of Morocco.

Background: β-thalassemia syndromes are the most common hereditary blood disorders in the world and are recognized as a major health problem in Morocco. They are characterized by the reduction or the absence of β-globin chain synthesis. The severity of the disease depends on the nature of the variants affecting the β-globin gene (HBB), and each ethnic group has its own mutation spectrum.

Clinical and genetic spectrums of 413 North African families with inherited retinal dystrophies and optic neuropathies.

Background: Inherited retinal dystrophies (IRD) and optic neuropathies (ION) are the two major causes world-wide of early visual impairment, frequently leading to legal blindness. These two groups of pathologies are highly heterogeneous and require combined clinical and molecular diagnoses to be securely identified. Exact epidemiological studies are lacking in North Africa, and genetic studies of IRD and ION individuals are often limited to case reports or to some families that migrated to the rest of the world.

Cancer/Testis Antigen 55 is required for cancer cell proliferation and mitochondrial DNA maintenance.

Cancer/Testis Antigens (CTAs) represent a group of proteins whose expression under physiological conditions is restricted to testis but activated in many human cancers. Also, it was observed that co-expression of multiple CTAs worsens the patient prognosis. Five CTAs were reported acting in mitochondria and we recently reported 147 transcripts encoded by 67 CTAs encoding for proteins potentially targeted to mitochondria.

Characterization of SSBP1-related optic atrophy and foveopathy.

Dominant optic atrophy (DOA) is genetically heterogeneous and most commonly caused by mutations in OPA1. To distinguish between the classical OPA1-related and the recently identified SSBP1-related DOAs, the retina and fovea of 27 patients carrying the SSBP1 p.Arg38Gln variant were scrutinized using 20° × 20° macular cube and 30° and 55° field fundus autofluorescence photographs.

Pathogenic variants cause a developmental ocular phenotype recapitulated in a mutant mouse model.

Pathogenic variants cause a rare autosomal dominant neurodevelopmental disorder referred to as the Bosch-Boonstra-Schaaf Optic Atrophy Syndrome. Although visual loss is a prominent feature seen in affected individuals, the molecular and cellular mechanisms contributing to visual impairment are still poorly characterized. We conducted a deep phenotyping study on a cohort of 22 individuals carrying pathogenic variants to document the neurodevelopmental and ophthalmological manifestations, in particular the structural and functional changes within the retina and the optic nerve, which have not been detailed previously.