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

Abstract

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. ANN NEUROL 2026;99:223-230.