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Background: Congenital myasthenic syndrome is a heterogeneous group of inherited neuromuscular transmission disorders. Variants in RAPSN are a common cause of CMS, accounting for approximately 14%–27% of all CMS cases. Whether preimplantation genetic testing for monogenic disease (PGT‐M) could be used to prevent the potential birth of CMS‐affected children is unclear. Methods: Application of WES (whole‐exome sequencing) for carrier testing and guidance for the PGT‐M in the absence of a genetically characterized index patient as well as assisted reproductive technology were employed to prevent the occurrence of birth defects in subsequent pregnancy. The clinical phenotypes of stillborn fetuses were also assessed. Results: The family carried two likely pathogenic variants in RAPSN(NM_005055.5): c.133G>A (p.V45M) and c.280G>A (p.E94K). And the potential birth of CMS‐affected child was successfully prevented, allowing the family to have offspring devoid of disease‐associated variants and exhibiting a normal phenotype. Conclusion: This report constitutes the first documented case of achieving a CMS‐free offspring through PGT‐M in a CMS‐affected family. By broadening the known variant spectrum of RAPSN in the Chinese population, our findings underscore the feasibility and effectiveness of PGT‐M for preventing CMS, offering valuable insights for similarly affected families. [ABSTRACT FROM AUTHOR]

Abstract Background Congenital myasthenic syndrome is a heterogeneous group of inherited neuromuscular transmission disorders. Variants in RAPSN are a common cause of CMS, accounting for approximately 14%–27% of all CMS cases. Whether preimplantation genetic testing for monogenic disease (PGT‐M) could be used to prevent the potential birth of CMS‐affected children is unclear. Methods Application of WES (whole‐exome sequencing) for carrier testing and guidance for the PGT‐M in the absence of a genetically characterized index patient as well as assisted reproductive technology were employed to prevent the occurrence of birth defects in subsequent pregnancy. The clinical phenotypes of stillborn fetuses were also assessed. Results The family carried two likely pathogenic variants in RAPSN(NM_005055.5): c.133G>A (p.V45M) and c.280G>A (p.E94K). And the potential birth of CMS‐affected child was successfully prevented, allowing the family to have offspring devoid of disease‐associated variants and exhibiting a normal phenotype. Conclusion This report constitutes the first documented case of achieving a CMS‐free offspring through PGT‐M in a CMS‐affected family. By broadening the known variant spectrum of RAPSN in the Chinese population, our findings underscore the feasibility and effectiveness of PGT‐M for preventing CMS, offering valuable insights for similarly affected families.

Objective: Congenital myasthenic syndrome (CMS) is a heterogeneous group of diseases that are not immune-mediated. It is caused by structural defects in different synaptic proteins of neuromuscular transmission as a result of different mutations. CMS is classified according to the location of the mutant protein as presynaptic, synaptic basal lamina-associated, or postsynaptic. In this study, we aimed to help further the knowledge of this issue by analyzing the clinical features and treatment responses of patients with an extremely rare condition of CMS. Methods: The clinical information of 13 patients who attended the CMS clinic at Mersin City Training and Research Hospital and Aydın Maternity and Child Hospital were reviewed. After considering the clinical diagnosis in all our cases, we performed a genetic diagnosis with whole exon sequencing or a CMS panel. Results: Of the 13 patients included in this study, 11 (84.6%) were males and 2 (15.4%) were females. The mean age of our patients was 73.30±60.56 months, and the mean age at the time of diagnosis was 44±49.15 months. In our patients diagnosed with CMS, 9 (69.2%) COLQ mutations, 2 (15.4%) CHAT mutations, 1 (7.7%) RAPSN mutation, and 1 (7.7%) SCN4A mutation were observed. Ephedrine was started in 8 of the 9 patients with COLQ mutations, and a good response was obtained. A good response to treatment was not observed in those patients who were started on pyridostigmine. Conclusion: CMS can often be confused with other neuromuscular diseases. In patients presenting with ptosis, bulbar findings, apnea, and muscle weakness, CMS should be prediagnosed, and a genetic examination should be performed on these patients. [ABSTRACT FROM AUTHOR]

Congenital myasthenic syndrome (CMS) is a clinically and genetically heterogeneous neuromuscular disorder characterized by muscle weakness and caused by mutations in more than 35 different genes. This condition should not be overlooked as a subset of patients with CMS are treatable. However, the diagnosis of CMS is often difficult due to the broad variability in disease severity and course. A five-year-old boy without remarkable family history was born with marked general muscle hypotonia and weakness, respiratory insufficiency, anomalies, and multiple joint contractures. Congenital myopathy was suspected based upon type 1 fiber predominance on muscle biopsy. However, he was diagnosed with CMS at age 4 years when his ptosis and ophthalmoplegia were found to be improved by edrophonium chloride and repetitive nerve stimulation showed attenuation of compound muscle action potentials. An exome sequencing identified a compound heterozygous missense variant of c.737C > T (p.A246V) and a novel intronic insertion c.1166 + 4_1166 + 5insAAGCCCACCAC in RAPSN. RT-PCR analysis which showed the skipping of exon 7 in a skeletal muscle sample confirmed that the intronic insertion was pathogenic. His myasthenic symptoms were remarkably improved by pyridostigmine. The patient's diagnosis of CMS was confirmed by exome sequencing, and RT-PCR revealed that the skipping of exon 7 in RAPSN was caused by a novel intronic insertion. The genetic information uncovered in this case should therefore be added to the collection of tools for diagnosing and treating CMS. [ABSTRACT FROM AUTHOR]

We here present the case of a patient with a congenital myasthenic syndrome (CMS) due to pathogenic variants in the RAPSN gene. During childhood he experienced recurrent episodes of respiratory failure during respiratory infections. This and other cases were reported as isolated dystrophy of the diaphragmatic musculature. In adulthood, whole exome sequencing revealed two heterozygous pathogenic variants in the RAPSN gene. This led to the revision of the diagnosis to rapsyn CMS11 (OMIM:616326, MONDO:0014588). EMG, muscle ultrasound and the revision of muscle biopsies taken in childhood support this diagnosis. After the revision of the diagnosis, treatment with pyridostigmine was started. This resulted in a reduction of fatigability and an improvement in functional abilities and quality of life.