A Novel Transcriptional Slippage Mechanism Rescues Dystrophin Expression from a DMD Frameshift Variant

Pathogenic DMD variants usually follow the reading‐frame rule: out‐of‐frame changes cause Duchenne muscular dystrophy, whereas in‐frame ones produce Becker muscular dystrophy (BMD). We report a 23‐year‐old man with BMD‐like weakness, calf hypertrophy, elevated creatine kinase, and dilated cardiomyopathy. A novel hemizygous c.2281delG variant converted an A₄GA₅ motif to A₉, predicting a frameshift; however, Western blot showed ~15% full‐length dystrophin. cDNA and polymerse chain reaction (PCR)‐free direct RNA sequencing demonstrated transcriptional slippage, adding 1 adenine (A₁₀) that restores the reading frame and dystrophin. This RNA‐level rescue of an out‐of‐frame DMD variant explains the mild phenotype and highlights the importance of transcript‐level analysis in dystrophinopathies.