Spectrum of DMD gene mutations in 507 patients: a retrospective genotype-phenotype study using next-generation sequencing.

Abstract

Background: Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, but comprehensive analyses of mutational patterns and clinical correlations remain limited.

Objective: To characterize the DMD mutational spectrum and its clinical implications in a large Asian cohort.

Methods & settings: A retrospective genetic analysis of 507 unrelated male DMD/Becker muscular dystrophy patients was conducted at Hunan Children's Hospital (2018-2021). Multiplex ligation-dependent probe amplification (MLPA) and next-generation sequencing (NGS) were employed for comprehensive variant detection. Variants were classified per ACMG/AMP guidelines.

Results: Exon deletions predominated (64.9%), followed by small mutations (26.0%) and duplications (9.1%). Nonsense mutations were the most frequent small variant (16.0%). Domain analysis revealed mutations clustered in the Central Rod Domain (CRD; exons 45-55). The Carboxy-Terminal Domain (CTD) was associated with the most severe phenotype (earliest loss of ambulation, P < 0.05 vs. Actin-Binding Domain [ABD] or CRD). Exon 53 skipping was applicable in 39.39% of eligible patients. De novo mutations accounted for 7.9% (40/507) of cases. Epilepsy comorbidity occurred in 1.34% (6/448) of DMD patients.

Conclusion: This study delineates the DMD mutational landscape in a Chinese cohort, highlighting domain-specific phenotypic severity (CTD > ABD > CRD) and identifying exon 53 as the primary therapeutic target for exon skipping. These findings enhance prognostic precision and guide targeted therapeutic strategies.