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Clinical, muscle imaging, and genetic characteristics of dystrophinopathies with deep-intronic DMD variants

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Abstract

Background

Phenotypic heterogeneity within or between families with a same deep-intronic splice-altering variant in the DMD gene has never been systematically analyzed. This study aimed to determine the phenotypic and genetic characteristics of patients with deep-intronic DMD variants.

Methods

Of 1338 male patients with a suspected dystrophinopathy, 38 were confirmed to have atypical pathogenic DMD variants via our comprehensive genetic testing approach. Of the 38 patients, 30 patients from 22 unrelated families with deep-intronic DMD variants underwent a detailed clinical and imaging assessment.

Results

Nineteen different deep-intronic DMD variants were identified in the 30 patients, including 15 with Duchenne muscular dystrophy (DMD), 14 with Becker muscular dystrophy (BMD), and one with X-linked dilated cardiomyopathy. Of the 19 variants, 15 were single-nucleotide variants, 2 were structural variants (SVs), and 2 were pure-intronic large-scale SVs causing aberrant inclusion of other protein-coding genes sequences into the mature DMD transcripts. The trefoil with single fruit sign was observed in 18 patients and the concentric fatty infiltration pattern was observed in 2 patients. Remarkable phenotypic heterogeneity was observed not only in skeletal but also cardiac muscle involvement in 2 families harboring a same deep-intronic variant. Different skeletal muscle involvement between families with a same variant was observed in 4 families. High inter-individual phenotypic heterogeneity was observed within two BMD families and one DMD family.

Conclusions

Our study first highlights the variable phenotypic expressivity of deep-intronic DMD variants and demonstrates a new class of deep-intronic DMD variants, i.e., pure-intronic SVs involving other protein-coding genes.

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Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article and its Supplementary Information.

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Funding

This study was supported by the Beijing Municipal Science and Technology Commission (Grant number Z191100006619034) and National Natural Science Foundation of China (Grant number 82201553).

Author information

Author notes

  1. Zhiying Xie and Chengyue Sun have contributed equally to the study (first authors).

  2. Isabelle Schrauwen, Zhaoxia Wang and Yun Yuan have contributed equally to the study (senior authors).

Authors and Affiliations

  1. Department of Neurology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, 100034, China

    Zhiying Xie, Chang Liu, Luhua Wei, Jiaxi Yu, Chen Ling, Meng Yu, Yinglin Leng, Lingchao Meng, Yunchuang Sun, Jianwen Deng, Zhaoxia Wang & Yun Yuan

  2. Department of Neurology, Peking University People’s Hospital, Beijing, 100044, China

    Chengyue Sun

  3. Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, 610041, China

    Zhihao Xie

  4. Department of Neurology, Beijing Jishuitan Hospital, Beijing, 100035, China

    Xuejun Guo

  5. Department of Pathology, Peking Union Medical College Hospital, Beijing, 100730, China

    Yilin Liu

  6. Department of Neurology, Center for Statistical Genetics, Sergievsky Center, Columbia University Medical Center, New York, NY, USA

    Suzanne M. Leal & Isabelle Schrauwen

Authors
  1. Zhiying Xie
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  2. Chengyue Sun
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  4. Zhihao Xie
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Contributions

ZX, CS, CL, ZX, SML, IS, ZW and YY contributed to the study conception and design. Material preparation and data collection were performed by ZX, CS, CL, JY, CL, XG, YL, MY, YL, LW, LM, YS and JD. Clinical and imaging data analysis was performed by ZX, CS, CL, JY, LW, LM, YS, JD, ZW and YY. Genetic data analysis was performed by ZX, CS, CL, ZX, ZW and YY. Bioinformatic analysis was performed by ZX, CS, ZX, SML and IS. Figure layout was performed by ZX, CS, CL, SML, IS, ZW and YY. The first draft of the manuscript was written by ZX and CS, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Yun Yuan.

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Conflicts of interest

The authors declare no conflict of interest.

Ethics statement

This study was approved by the Ethics Committee at Peking University First Hospital (2019181). Informed consent was obtained from adult patients or parents/guardians of minors included in the study cohort.

Supplementary Information

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Supplementary file1 (PDF 6402 KB)

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Xie, Z., Sun, C., Liu, C. et al. Clinical, muscle imaging, and genetic characteristics of dystrophinopathies with deep-intronic DMD variants. J Neurol 270, 925–937 (2023). https://doi.org/10.1007/s00415-022-11432-0

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  • DOI: https://doi.org/10.1007/s00415-022-11432-0

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