Uncovering the true features of dystrophin gene rearrangement and improving the molecular diagnosis of Duchenne and Becker muscular dystrophies

Duchenne and Becker muscular dystrophies (DMD/BMD) are caused by complex mutations in the dystrophin gene (DMD). Currently, there is no integrative method for the precise detection of all potential DMD variants, a gap which we aimed to address using long-read sequencing. The captured long-read sequencing panel developed in this study was applied to 129 subjects, including 11 who had previously unsolved cases. The results showed that this method accurately detected DMD mutations, ranging from single-nucleotide variations to structural variations. Furthermore, our findings revealed that continuous exon duplication/deletion in the DMD/BMD cohort may be attributed to complex segmental rearrangements and that noncontiguous duplication/deletion is generally attributed to intragenic inversion or interchromosome translocation. Mutations in the deep introns were confirmed to produce a pseudoexon. Moreover, variations in female carriers were precisely identified. The integrated and precise DMD gene screening method proposed in this study could improve the molecular diagnosis of DMD/BMD. [Display omitted] •Long-read sequencing can detect DMD mutations that involve both SNVs and complex SVs•Non-contiguous changes due to intragenic inversion or interchromosome translocation•Deep intron mutations generate pseudoexons, advancing DMD/BMD genetics•The findings could enhance diagnoses and inform clinicians and researchers Health sciences; Clinical genetics; Pediatrics