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

Chao Ling; Yi Dai; Chang Geng; Shirang Pan; Weipeng Quan; Qingyun Ding; Xunzhe Yang; Dongchao Shen; Qing Tao; Jingjing Li; Jia Li; Yinbing Wang; Shan Jiang; Yang Wang; Lin Chen; Liying Cui; Depeng Wang

doi:10.1016/j.isci.2023.108365

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

iScience. 2023 Oct 30;26(12):108365. doi: 10.1016/j.isci.2023.108365. eCollection 2023 Dec 15.

Authors

Chao Ling^{1

2}, Yi Dai³, Chang Geng³, Shirang Pan⁴, Weipeng Quan⁴, Qingyun Ding³, Xunzhe Yang³, Dongchao Shen³, Qing Tao⁴, Jingjing Li⁴, Jia Li³, Yinbing Wang³, Shan Jiang³, Yang Wang⁴, Lin Chen³, Liying Cui³, Depeng Wang⁴

Affiliations

¹ The Laboratory of Clinical Genetics, Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100730, China.
² State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100730, China.
³ Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100730, China.
⁴ Grandomics Biosciences, Beijing 102200, China.

Abstract

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.

Keywords: Clinical genetics; Health sciences; Pediatrics.