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. RESULTS: We identified two novel LTBP3 homozygous variants, the c.2495delT deletion (p.Phe832SerfsTer36) and the c.3716 G>A (p.Cys1239Tyr) missense variant, respectively. Molecular modelling and stability analyses of the missense variant disclosed a possible destabilization of the wild-type structure. CONCLUSION: Although LTBP3 variants were related to this phenotype in various populations, we report the first LTBP3 variants in the Moroccan population, in families with Hypoplastic Amelogenesis Imperfecta.

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. In order to improve the knowledge of their clinical and genetic spectrums in North Africa, we reviewed published data, to illustrate the most prevalent pathologies, genes and mutations encountered in this geographical region, extending from Morocco to Egypt, comprising 200 million inhabitants. MAIN BODY: We compiled data from 413 families with IRD or ION together with their available molecular diagnosis. The proportion of IRD represents 82.8% of index cases, while ION accounted for 17.8%. Non-syndromic IRD were more frequent than syndromic ones, with photoreceptor alterations being the main cause of non-syndromic IRD, represented by retinitis pigmentosa, Leber congenital amaurosis, and cone-rod dystrophies, while ciliopathies constitute the major part of syndromic-IRD, in which the Usher and Bardet Biedl syndromes occupy 41.2% and 31.1%, respectively. We identified 71 ION families, 84.5% with a syndromic presentation, while surprisingly, non-syndromic ION are scarcely reported, with only 11 families with autosomal recessive optic atrophies related to OPA7 and OPA10 variants, or with the mitochondrial related Leber ION. Overall, consanguinity is a major cause of these diseases within North African countries, as 76.1% of IRD and 78.8% of ION investigated families were consanguineous, explaining the high rate of autosomal recessive inheritance pattern compared to the dominant one. In addition, we identified many founder mutations in small endogamous communities. SHORT CONCLUSION: As both IRD and ION diseases constitute a real public health burden, their under-diagnosis in North Africa due to the absence of physicians trained to the identification of inherited ophthalmologic presentations, together with the scarcity of tools for the molecular diagnosis represent major political, economic and health challenges for the future, to first establish accurate clinical diagnoses and then treat patients with the emergent therapies.

A homozygous nonsense HECW2 variant is associated with neurodevelopmental delay and intellectual disability.

Intellectual disability is characterized by a significant impaired intellectual and adaptive functioning, affecting approximately 1-3% of the population, which can be caused by a variety of environmental and genetic factors. In this respect, de novo heterozygous HECW2 variants were associated recently with neurodevelopmental disorders associated to hypotonia, seizures, and absent language. HECW2 encodes an E3 ubiquitin-protein ligase that stabilizes and enhances transcriptional activity of p73, a key factor regulating proliferation, apoptosis, and neuronal differentiation, which are together essential for proper brain development. Here, using whole exome sequencing, we identified a homozygous nonsense HECW2 variant: c.736C > T; p.Arg246* in a proband from a Moroccan consanguineous family, with developmental delay, intellectual disability, hypotonia, generalized tonico-clonic seizures and a persistent tilted head. Thus this study describes the first homozygous HECW2 variant, inherited as an autosomal recessive pattern, contrasting with former reported de novo variants found in HECW2 patients.

Identification of novel mutations by targeted NGS in Moroccan families clinically diagnosed with a neuromuscular disorder.

BACKGROUND AND AIMS: The identification of underlying genes of genetic conditions has expanded greatly in the past decades, which has broadened the field of genes responsible for inherited neuromuscular diseases. We aimed to investigate mutations associated with neuromuscular disorders phenotypes in 2 Moroccan families. MATERIAL AND METHODS: Next-generation sequencing combined with Sanger sequencing could assist with understanding the hereditary variety and underlying disease mechanisms in these disorders. RESULTS: Two novel homozygous mutations were described in this study. The SIL1 mutation is the first identified in the Moroccan population, the mutation was identified as the main cause of Marinesco-Sjogren syndrome in one patient. While the second mutation identified in the fatty acid 2-hydroxylase gene (FA2H) was associated with the Spastic paraplegia 35 in another patient, both transmitted in an autosomal recessive pattern. DISCUSSION AND CONCLUSIONS: These conditions are extremely rare in the North African population and may be underdiagnosed due to overlapping clinical characteristics and heterogeneity of these diseases. We have reported in this study mutations associated with the diseases found in the patients. In addition, we have narrowed the phenotypic spectrum, as well as the diagnostic orientation of patients with neuromuscular disorders, who might have very similar symptoms to other disease groups.

Clinical and genetic investigations of three Moroccan families with retinitis pigmentosa phenotypes.

Purpose: Progressive inherited retinal dystrophies, characterized by degeneration of rod photoreceptors and then cone photoreceptors, are known as retinitis pigmentosa (RP), for which 89 genes have been identified. Today, only five Moroccan families with RP with a genetic diagnosis have been reported, justifying our investment in providing further clinical and genetic investigations of families with RP in Morocco. Methods: The clinical diagnosis based on a combination of a history of night blindness, abnormal rod or rod-cone responses in electroretinography (ERG), and constricted visual field or difficulty perceiving side objects identified three Moroccan families with an RP phenotype. Probands of these families underwent whole exome sequencing (WES), and candidate variants were evaluated for their segregation within family members. Results: All patients had a history of night blindness and unrecordable rod and cone ERG traces. In addition, one patient had cystoid macular edema, and another had discrete autofluorescence abnormalities, in addition to ellipsoid zone disorganization and narrowed retinal vessels. WES sequencing revealed heterozygous compound mutations in CRB1:c.1690G>T//c.1913C>T and in ABCA4:c.5908C>T//c.6148G>C and a homozygous PDE6B splice mutation c.1920+2T>C. Conclusions: We provide the first description of Moroccan patients with the RP phenotype harboring pathogenic mutations in the CRB1 and ABCA4 genes and the second description of an individual with RP with a PDE6B mutation, associated with cystoid macular edema. These data contribute to expand the genetic diagnosis of RP phenotypes in Morocco.

A homozygous MPZL2 deletion is associated with non syndromic hearing loss in a moroccan family.

Adhesion glycoproteins are implicated in the pathophysiology of hearing loss, the most frequent inherited sensory disorder, affecting 1 in 1000 new-borns. Exome sequencing of a consanguineous Moroccan patient with mild hearing loss identified for the first time in a North African family a single homozygous mutation c.72delA in MPZL2 gene, encoding the Myelin Protein Zero-Like 2, reported as causing deafness in two other populations. Variable tandem repeat genotyping of this family revealed that the c.72delA MPZL2 allele shared a common haplotype with Turkish and Dutch families. These results confirm the pathogenicity of this MPZL2 mutation in recessive mild to moderate non-syndromic deafness.