Clin Chem. 2025 Nov 7:hvaf136. doi: 10.1093/clinchem/hvaf136. Online ahead of print.
ABSTRACT
BACKGROUND: Duchenne and Becker muscular dystrophies are X-linked neuromuscular disorders caused by mutations in the dystrophin gene (DMD). Duplications account for approximately 10% of pathogenic variants, but their structural complexity and variable clinical impact present significant challenges in pathogenicity interpretation.
METHODS: We retrospectively analyzed whole exome sequencing and multiplex ligation-dependent probe amplification data from 3842 individuals, identifying 39 patients with DMD duplications. These patients underwent whole genome sequencing (WGS) to characterize duplication patterns, breakpoint features, and haplotype structures. Optical genome mapping (OGM) was additionally performed in WGS-unresolved cases to identify exact haplotypes. We also compared the diagnostic performance of different platforms and further investigated genotype-phenotype correlations.
RESULTS: DMD duplications exhibited substantial structural heterogeneity and were characterized into 4 major patterns: tandem duplication (58%), duplication-normal-duplication (16%), duplication-inversion-duplication (16%), and intricate duplication (10%). Recurrent complex arrangements were associated with high-homology repeats and often extended beyond DMD, complicating haplotype interpretation. WGS alone failed to resolve haplotypes in 34% (13/38) of cases, while OGM missed certain exon duplications and small fragments in 33% of cases (2/6). Integration of WGS and OGM enabled precise haplotype reconstruction and improved genotype-phenotype correlation.
CONCLUSIONS: Our findings broaden the molecular spectrum of DMD duplications, highlight their widespread structural complexity, and emphasize the importance of integrating multiple technologies to precisely delineate duplication haplotype structures and assess the pathogenicity of variants with uncertain significance. These findings provide valuable insights for DMD duplication detection, pathogenicity evaluation, and genetic counseling.
PMID:41206630 | DOI:10.1093/clinchem/hvaf136