Novel DMD Frameshift Variant (p.Leu2017Profs*5) in Spectrin-Like Repeat 16 Expands the Mutational Spectrum of DMD

Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disorder caused by pathogenic variants in the DMD gene, which encodes dystrophin, a cytoskeletal protein linking intracellular actin to the extracellular matrix via the dystrophin-associated protein complex and maintaining muscle fiber integrity. With the emergence of disease-modifying therapies, early and accurate molecular diagnosis is increasingly important. Whole-exome sequencing (WES) is widely used to evaluate unexplained hyperCKemia and distinguish DMD from other inherited neuromuscular disorders.

WES identified a novel hemizygous frameshift variant in DMD (NM_004006.3:c.6050_6051del; p.Leu2017Profs*5) in a Taiwanese boy with markedly elevated creatine kinase levels (> 10,000 U/L) and clinical features consistent with DMD. The variant was classified as likely pathogenic according to ACMG criteria (PVS1, PS2, PP3). Comparative genomic analysis demonstrated strong evolutionary conservation at the variant site within the 16th spectrin-like repeat (exon 42), with phastCons scores of 1 and phyloP scores of +2.925 and +1.015. AlphaFold-based structural modeling suggested disruption of the three-helix bundle architecture, while CHARMM-based energy analysis suggested a potential destabilizing effect that appeared more consistent with previously reported pathogenic exon 42 frameshift variants than with benign missense variants at the same locus.

This is the first reported case of DMD associated with the novel frameshift variant c.6050_6051del (p.Leu2017Profs*5). Integrated genomic, evolutionary, and structural analyses support the likely pathogenic interpretation of this variant. This study expands the mutational spectrum of DMD and highlights the value of combining WES with structure-informed approaches for variant interpretation. These findings provide preliminary structural insights into the potential effects of the identified variant and highlight the possible utility of structure-informed variant interpretation in the absence of functional assays.