Key result
Next-generation sequencing provided a definitive molecular diagnosis in 80.95% of families with congenital muscular dystrophies and myopathies, identifying 16 pathogenic variants including two novel LAMA2 mutations.
Why the study?
Congenital muscular dystrophies and congenital myopathies are clinically and genetically heterogeneous disorders, prompting a genetic and molecular characterization in Moroccan patients.
Observational (n=23)
No
Next-generation sequencing is a highly effective first-line diagnostic tool for congenital muscular dystrophies and myopathies, yielding a genetic diagnosis in ~81% of a Moroccan cohort.
Supports NGS as first-line testing for congenital myopathies; leaves open generalizability beyond this cohort.
Background Congenital muscular dystrophies (CMD) and congenital myopathies (CM) are clinically and genetically heterogeneous groups of neuromuscular disorders resulting in prenatal or early-onset hypotonia, muscle weakness, myogenic pattern, and dystrophic or myopathic features on muscle biopsy. In this study, we provide a genetic and molecular characterization of CMD and CM in Moroccan patients. Patients and methods In this cohort, we investigated 23 Moroccan patients from 21 families who consented to genetic testing. Firstly, genetic analysis in the probands was conducted by next-generation sequencing (NGS) technology using two approaches: targeted NGS gene panel and clinical exome sequencing to study the mutational spectrum and to achieve an accurate diagnosis of these hereditary myopathies in Morocco. Results NGS data analysis revealed 16 pathogenic variants harbored in 17 unrelated patients that were genetically resolved. The phenotypic forms identified were in order: LAMA2 -related CMD (52.94%), LMNA -CMD (23.53%), and RYR1 -related congenital myopathy (17.65%). The congenital titinopathy group was less frequent (5.88%). Here, we identified two novel recessive variants in LAMA2 gene: c.2164G > A (p.Glu722Lys), and c.(6992 + 1_6993-1)_(7300 + 1_7301-1)del p.(Pro2332Glnfs*10). Additionally, we expanded the phenotypic spectrum of a known heterozygous LMNA c.1718C > T p.(Ser573Leu) variant, and we report it for the first time to a form of CMD. Conclusions The introduction of the NGS tool in clinical practice allowed us to improve the diagnosis and the management of these neuromuscular diseases and to highlight the importance of molecular genetic diagnosis of these disorders that are underestimated in the Moroccan population.
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Kadiri et al. (2023) conducted an observational in Congenital muscular dystrophies and congenital myopathies (n=23). Next-generation sequencing was evaluated on Diagnostic yield (proportion of genetically resolved families). Next-generation sequencing provided a definitive molecular diagnosis in 80.95% of families with congenital muscular dystrophies and myopathies, identifying 16 pathogenic variants including two novel LAMA2 mutations.
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