Clinical and Genetic Heterogeneity of Congenital Myasthenic Syndromes: Insights From a Large Cohort

ABSTRACT Aim Congenital myasthenic syndromes (CMS) represent an ultra‐rare group of neuromuscular disorders. The most frequently implicated genes in CMS etiology include CHRNE, RAPSN, DOK7, COLQ, and CHAT. Methods and Results In this study, we aimed to contribute novel data to the literature to enhance genotype–phenotype correlations in CMS. Molecular genetic analysis data from 787 patients were evaluated, and 29 distinct variants were identified in 29 individuals. Fourteen patients carried homozygous or compound heterozygous variants in CHRNE (5 patients), PLEC (2 patients), CHRND (1 patient), RAPSN (1 patient), DOK7 (1 patient), SCN4A (1 patient), CHAT (1 patient), COLQ (1 patient), and GMPPB (1 patient) genes. Variants accounting for the clinical features were confirmed in only 14 patients (1.7%) of the cohort, with 65% of these variants detected in the five most common genes. Conclusion Overall, our findings suggest that although CMS is a clinically heterogeneous group, targeted NGS panels should be prioritized for patients presenting with characteristic features such as ptosis, respiratory distress, hypotonia, and joint contractures. Nevertheless, given the phenotypic overlap of CMS with other neuromuscular disorders, broader molecular approaches such as whole‐exome sequencing may also be required. Furthermore, the identification of additional contributors, including potential modifier genes, is essential for accurate diagnosis, effective genetic counseling, and future therapeutic strategies.