Phenotypic Diversity in Pediatric Congenital Myasthenic Syndrome: Insights from CHRNE and DPAGT1 Variants

Introduction: Congenital myasthenic syndrome (CMS) is a rare hereditary disorder of the neuromuscular junction caused by pathogenic variants that affect acetylcholine transmission. We report three pediatric cases with CMS, including a rare homozygous CHRNE mutation previously described only once, a novel CHRNE compound heterozygous variant, and two novel DPAGT1 variants associated with limb-girdle CMS (LG-CMS), thereby expanding the known genetic and phenotypic spectrum of the disorder. Case presentation: The first patient, a 4-year-old girl born to consanguineous parents, presented with bilateral ptosis and fatigable weakness since infancy. Whole-genome sequencing revealed a homozygous CHRNE variant, c.991C>T. The second patient, a 4-year-old boy born to non-consanguineous parents, presented with congenital bilateral ptosis and ophthalmoplegia without generalized weakness. Genetic analysis identified compound heterozygous CHRNE variants, c.905C>G and c.1040T>C. Both patients demonstrated marked improvement with pyridostigmine therapy. The third patient, a 3-year-old girl born to non-consanguineous parents, presented with severe limb weakness requiring assistance in walking and performing daily activities with minimal ocular involvement, suggesting a diagnosis of LG-CMS. Genetic testing identified two novel variants in the DPAGT1 gene in the compound heterozygous form, c.710G>T and c.858C>A. The initial response to pyridostigmine diminished over time. Conclusions: These cases underscore the phenotypic heterogeneity of CMS, even within the same genetic subtype, and expand the existing mutational spectrum of CHRNE and DPAGT1 genes. This study also highlights the essential role of molecular diagnosis in distinguishing CMS from other neuromuscular disorders. Early genetic confirmation facilitates genotype-targeted therapy, prevents inappropriate immunosuppression, and enables informed reproductive counseling.