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已发表论文
结合长读长测序逐步诊断策略解读杜氏肌营养不良症表型 - 基因型不一致性的研究
Authors Yuan Q , Liu C, Lu Y, Han X, Wang Z, Yuan Y, Xie Z
Received 7 June 2025
Accepted for publication 4 November 2025
Published 25 November 2025 Volume 2025:18 Pages 243—249
DOI https://doi.org/10.2147/TACG.S544691
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Prof. Dr. Martin Maurer
Qingyue Yuan, Chang Liu, Yanyu Lu, Xu Han, Zhaoxia Wang, Yun Yuan,* Zhiying Xie*
Department of Neurology, Peking University First Hospital, Beijing, 100034, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Zhiying Xie, Department of Neurology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, 100034, People’s Republic of China, Email xiezhiyingxzy@163.com Yun Yuan, Department of Neurology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, 100034, People’s Republic of China, Email yuanyun2002@126.com
Introduction: Pathogenic variants in the DMD gene maintaining the open reading frame typically cause Becker muscular dystrophy. Here, we report a 7.7-year-old boy exhibiting a severe Duchenne muscular dystrophy phenotype, despite an in-frame deletion of DMD exons 50– 51 identified by initial genetic testing, representing a notable exception to the conventional reading-frame rule.
Methods: To elucidate his phenotype-genotype discordance, muscle biopsy and subsequent dystrophin protein and mRNA analyses were conducted, followed by long-read sequencing of DMD gene and splicing analysis.
Results: Muscle biopsy revealed a dystrophic pattern and negative expression of dystrophin-N and dystrophin-C. The dystrophin mRNA analysis identified two out-of-frame DMD transcripts, which were different from the in-frame deletion of DMD exons 50– 51 and can explain his severe phenotype. Long-read sequencing uncovered a novel deletion variant (~97kb) in DMD gene, which produced the two out-of-frame transcripts through aberrant splicing.
Conclusion: This case underscores the necessity of a stepwise molecular analysis strategy for the interpretation of phenotype-genotype discordance in dystrophinopathy. This stepwise diagnostic approach is essential for accurately characterizing DMD variants, guiding patient management, and genetic counseling.
Keywords: dystrophinopathy, phenotype-genotype discordance, reading-frame rule
Department of Neurology, Peking University First Hospital, Beijing, 100034, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Zhiying Xie, Department of Neurology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, 100034, People’s Republic of China, Email xiezhiyingxzy@163.com Yun Yuan, Department of Neurology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, 100034, People’s Republic of China, Email yuanyun2002@126.com
Introduction: Pathogenic variants in the DMD gene maintaining the open reading frame typically cause Becker muscular dystrophy. Here, we report a 7.7-year-old boy exhibiting a severe Duchenne muscular dystrophy phenotype, despite an in-frame deletion of DMD exons 50– 51 identified by initial genetic testing, representing a notable exception to the conventional reading-frame rule.
Methods: To elucidate his phenotype-genotype discordance, muscle biopsy and subsequent dystrophin protein and mRNA analyses were conducted, followed by long-read sequencing of DMD gene and splicing analysis.
Results: Muscle biopsy revealed a dystrophic pattern and negative expression of dystrophin-N and dystrophin-C. The dystrophin mRNA analysis identified two out-of-frame DMD transcripts, which were different from the in-frame deletion of DMD exons 50– 51 and can explain his severe phenotype. Long-read sequencing uncovered a novel deletion variant (~97kb) in DMD gene, which produced the two out-of-frame transcripts through aberrant splicing.
Conclusion: This case underscores the necessity of a stepwise molecular analysis strategy for the interpretation of phenotype-genotype discordance in dystrophinopathy. This stepwise diagnostic approach is essential for accurately characterizing DMD variants, guiding patient management, and genetic counseling.
Keywords: dystrophinopathy, phenotype-genotype discordance, reading-frame rule