Molecular diagnosis of dystrophinopathies in Morocco and report of six novel mutations

Kadiri, Youssef El; Selouani, Yassir; Ratbi, Ilham; Lyahyai, Jaber; Zrhidri, Abdelali; Sahli, Maryem; Ouhenach, Mouna; Jaouad, Imane Cherkaoui; Sefiani, Abdelaziz; Sbiti, Aziza

doi:10.1016/j.cca.2020.03.018

Cited by 3 publications

(5 citation statements)

References 34 publications

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“…On the other hand, nearly half (∼45%) of the total number of isoforms in patients with BMD are in-frame and wild-type. These findings do not contradict the reading frame rule and align with previous studies (9, 77, 78).…”

Section: Discussionsupporting

confidence: 92%

“…The subsequent frameshift and premature stop codon can explain the severe phenotype observed in the affected individual, which is described as DMD (9). On the other hand, the missense variant c.9973A>T results in incomplete aberrant splicing, with some amounts of the full-length transcript (28%), which is consistent with milder phenotypes observed in patients according to the study by Kadiri et al (77).…”

Section: Discussionsupporting

confidence: 82%

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Revision of splicing variants in theDMDgene

Davydenko,

Filatova,

Skoblov

2024

Preprint

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Background: Pathogenic variants in the dystrophin (DMD) gene lead to X-linked recessive Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). Nucleotide variants that affect splicing are a known cause of hereditary diseases. However, their representation in the public genomic variation databases is limited due to the low accuracy of their interpretation, especially if they are located within exons. The analysis of splicing variants in the DMD gene is essential both for understanding the underlying molecular mechanisms of the dystrophinopathies' pathogenesis and selecting suitable therapies for patients. Results: Using deep in silico mutagenesis of the entire DMD gene sequence and subsequent SpliceAI splicing predictions, we identified 7,948 DMD single nucleotide variants that could potentially affect splicing, 863 of them were located in exons. Next, we analyzed over 1,300 disease-associated DMD SNVs previously reported in the literature (373 exonic and 956 intronic) and intersected them with SpliceAI predictions. We predicted that ~95% of the intronic and ~10% of the exonic reported variants could actually affect splicing. Interestingly, the majority (75%) of patient-derived intronic variants were located in the AG-GT terminal dinucleotides of the introns, while these positions accounted for only 13% of all intronic variants predicted in silico. Of the 97 potentially spliceogenic exonic variants previously reported in patients with dystrophinopathy, we selected 38 for experimental validation. For this, we developed and tested a minigene expression system encompassing 27 DMD exons. The results showed that 35 (19 missense, 9 synonymous, and 7 nonsense) of the 38 DMD exonic variants tested actually disrupted splicing. We compared the observed consequences of splicing changes between variants leading to severe Duchenne and milder Becker muscular dystrophy and showed a significant difference in their distribution. This finding provides extended insights into relations between molecular consequences of splicing variants and the clinical features. Conclusions: Our comprehensive bioinformatics analysis, combined with experimental validation, improves the interpretation of splicing variants in the DMD gene. The new insights into the molecular mechanisms of pathogenicity of exonic single nucleotide variants contribute to a better understanding of the clinical features observed in patients with Duchenne and Becker muscular dystrophy.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 82%

Revision of splicing variants in theDMDgene

Davydenko,

Filatova,

Skoblov

2024

Preprint

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“…Because GNE play a key role in sialic acid production, several studies concentrated on potential for changes in sialylation of cell surface glycoproteins and glycolipids. Whereas hyposialylation has been revealed, the linkage between disease severity and diminution of the overall sialylation of muscle cells is insignificant (31) (18).…”

Section: Discussionmentioning

confidence: 99%

“…There are 5 to 8% of patients that present exon duplications (14), while small variants account for 10% to 30% which one third are de novo (15). Pathogenic DMD variants were previously identified in Moroccan patients (16)(17)(18)(19). In this study, using whole exome sequencing (WES) for molecular analysis of two Moroccan families, we identified respectively a homozygous variant (p.Arg 246Trp) in GNE related myopathy and a hemizygous (p. Arg2905Ter) in DMD related muscular dystrophy.…”

Section: Introductionmentioning

confidence: 86%

GNE Myopathy and Duchenne Muscular Dystrophy in Two Moroccans Families

Sifeddine,

Amalou,

Charif

et al. 2023

Muscle Ligaments and Tendons J

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Background. Hereditary myopathies and muscular dystrophies encompass a diverse group of disorders sharing common clinical features, including muscle weakness, motor developmental delays, and respiratory and bulbar dysfunction. This study aimed to investigate the genetic basis of myopathy in two Moroccan families presenting with these clinical features. Material and methods. Whole exome sequencing (WES) was employed as the primary method for genetic analysis in the two Moroccan families with myopathy symptoms. Candidate variants were confirmed by Sanger sequencing in all DNA available family members. In addition, computational analysis was utilized to assess the impact of the identified variant on the corresponding protein.Results. In the first family, the identified variant in the GNE gene, a homozygous missense substitution (p.Arg246Trp), was associated with GNE myopathy. In the second family, a hemizygous nonsense variant (p.Arg2905Ter) in the DMD gene was identified in the proband, who exhibited symptoms consistent with Duchenne Muscular Dystrophy (DMD). The molecular analysis confirmed the pathogenicity of the identified variants in both GNE myopathy and DMD. The missense variant (p.Arg246Trp) in the GNE gene was found to affect the stability and amino acid interactions of the GNE protein, thus implicating it in GNE myopathy. Additionally, the nonsense variant (p.Arg2905Ter) in the DMD gene provided genetic confirmation of DMD in the second family. Conclusions. This study represents the first genetically confirmed report of GNE myopathy in Morocco, emphasizing the significance of genetic analysis in diagnosing hereditary muscle disorders. The findings also underscore the importance of considering GNE myopathy as part of the differential diagnosis for patients presenting with slowly progressive distal lower extremity weakness. Overall, these results contribute to our understanding of the genetic basis of hereditary myopathies and muscular dystrophies in the Moroccan population.

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“…Patients with LGMD ( n = 67) were reported from Mali with onset predominantly in the first decade but the group lacked access to genetic diagnostic closure ( 24 ). North African countries are more resourced for access to genetic testing, as illustrated by researchers from Morocco who identified six novel pathogenic variants in the DMD gene following whole dystrophin gene sequencing ( 25 ). The perception that novel variants are prevalent in Africa are supported by various case reports ( 17 , 26 – 29 ).…”

Section: Paediatric Nmd In the South African Populationsmentioning

confidence: 99%

A case for genomic medicine in South African paediatric patients with neuromuscular disease

et al. 2022

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Paediatric neuromuscular diseases are under-recognised and under-diagnosed in Africa, especially those of genetic origin. This may be attributable to various factors, inclusive of socioeconomic barriers, high burden of communicable and non-communicable diseases, resource constraints, lack of expertise in specialised fields and paucity of genetic testing facilities and biobanks in the African population, making access to and interpretation of results more challenging. As new treatments become available that are effective for specific sub-phenotypes, it is even more important to confirm a genetic diagnosis for affected children to be eligible for drug trials and potential treatments. This perspective article aims to create awareness of the major neuromuscular diseases clinically diagnosed in the South African paediatric populations, as well as the current challenges and possible solutions. With this in mind, we introduce a multi-centred research platform (ICGNMD), which aims to address the limited knowledge on NMD aetiology and to improve genetic diagnostic capacities in South African and other African populations.

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Molecular diagnosis of dystrophinopathies in Morocco and report of six novel mutations

Cited by 3 publications

References 34 publications

Revision of splicing variants in theDMDgene

Revision of splicing variants in theDMDgene

GNE Myopathy and Duchenne Muscular Dystrophy in Two Moroccans Families

A case for genomic medicine in South African paediatric patients with neuromuscular disease

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