Adult-onset PLEC-related congenital myasthenic syndrome-myopathy overlap with upper limb predominant weakness

Congenital myasthenic syndromes (CMS) are genetically heterogeneous disorders in which precise molecular diagnosis is essential for management. Pathogenic variants in PLEC are a rare cause of autosomal recessive CMS and are frequently associated with epidermolysis bullosa simplex (EBS). We report an adult-onset case with EBS from birth, upper limb–predominant weakness, combined myopathic and myasthenic features, and subtle cardiomyopathy. Initial CMS gene panel testing identified a heterozygous canonical splice-site variant in PLEC. Subsequent trio exome sequencing revealed a second heterozygous intronic variant in trans, and RNA analysis demonstrated intron retention resulting in a frameshift, enabling variant reclassification and definitive diagnosis. This case expands the phenotypic spectrum of PLEC-related disease and highlights the value of transcript-level analysis in resolving cryptic Mendelian disorders.