Clinical and genetic interpretation of uncertain DMD missense variants: evidence from mRNA and protein studies
Abstract Background Pathogenic missense variants in the dystrophin (DMD) gene are rarely reported in dystrophinopathies. Most DMD missense variants are of uncertain significance and their pathogenicity interpretation remains complicated. We aimed to investigate whether DMD missense variants would ca...
Ausführliche Beschreibung
Autor*in: |
Zhiying Xie [verfasserIn] Chang Liu [verfasserIn] Haiyan Yu [verfasserIn] Zhihao Xie [verfasserIn] Chengyue Sun [verfasserIn] Ying Zhu [verfasserIn] Xiaoyu Hu [verfasserIn] Li Bai [verfasserIn] Luhua Wei [verfasserIn] Peng Sun [verfasserIn] Yanyu Lu [verfasserIn] Yunlong Lu [verfasserIn] Yawen Zhao [verfasserIn] Wei Zhang [verfasserIn] Zhaoxia Wang [verfasserIn] Lingchao Meng [verfasserIn] Yun Yuan [verfasserIn] |
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E-Artikel |
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Sprache: |
Englisch |
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2024 |
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In: Orphanet Journal of Rare Diseases - BMC, 2006, 19(2024), 1, Seite 13 |
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Übergeordnetes Werk: |
volume:19 ; year:2024 ; number:1 ; pages:13 |
Links: |
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DOI / URN: |
10.1186/s13023-024-03128-7 |
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Katalog-ID: |
DOAJ095651144 |
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520 | |a Abstract Background Pathogenic missense variants in the dystrophin (DMD) gene are rarely reported in dystrophinopathies. Most DMD missense variants are of uncertain significance and their pathogenicity interpretation remains complicated. We aimed to investigate whether DMD missense variants would cause aberrant splicing and re-interpret their pathogenicity based on mRNA and protein studies. Methods Nine unrelated patients who had an elevated serum creatine kinase level with or without muscle weakness were enrolled. They underwent a detailed clinical, imaging, and pathological assessment. Routine genetic testing and muscle-derived mRNA and protein studies of dystrophin and sarcoglycan genes were performed in them. Results Three of the 9 patients presented with a Duchenne muscular dystrophy (DMD) phenotype and the remaining 6 patients had a suspected diagnosis of Becker muscular dystrophy (BMD) or sarcoglycanopathy based on their clinical and pathological characteristics. Routine genetic testing detected only 9 predicted DMD missense variants in them, of which 6 were novel and interpreted as uncertain significance. Muscle-derived mRNA studies of sarcoglycan genes didn’t reveal any aberrant transcripts in them. Dystrophin mRNA studies confirmed that 3 predicted DMD missense variants (c.2380G < C, c.4977C < G, and c.5444A < G) were in fact splicing and frameshift variants due to aberrant splicing. The 9 DMD variants were re-interpreted as pathogenic or likely pathogenic based on mRNA and protein studies. Therefore, 3 patients with DMD splicing variants and 6 patients with confirmed DMD missense variants were diagnosed with DMD and BMD, respectively. Conclusion Our study highlights the importance of muscle biopsy and aberrant splicing for clinical and genetic interpretation of uncertain DMD missense variants. | ||
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10.1186/s13023-024-03128-7 doi (DE-627)DOAJ095651144 (DE-599)DOAJ86acb045fc3d4749a3f4198b0d35e13c DE-627 ger DE-627 rakwb eng Zhiying Xie verfasserin aut Clinical and genetic interpretation of uncertain DMD missense variants: evidence from mRNA and protein studies 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Pathogenic missense variants in the dystrophin (DMD) gene are rarely reported in dystrophinopathies. Most DMD missense variants are of uncertain significance and their pathogenicity interpretation remains complicated. We aimed to investigate whether DMD missense variants would cause aberrant splicing and re-interpret their pathogenicity based on mRNA and protein studies. Methods Nine unrelated patients who had an elevated serum creatine kinase level with or without muscle weakness were enrolled. They underwent a detailed clinical, imaging, and pathological assessment. Routine genetic testing and muscle-derived mRNA and protein studies of dystrophin and sarcoglycan genes were performed in them. Results Three of the 9 patients presented with a Duchenne muscular dystrophy (DMD) phenotype and the remaining 6 patients had a suspected diagnosis of Becker muscular dystrophy (BMD) or sarcoglycanopathy based on their clinical and pathological characteristics. Routine genetic testing detected only 9 predicted DMD missense variants in them, of which 6 were novel and interpreted as uncertain significance. Muscle-derived mRNA studies of sarcoglycan genes didn’t reveal any aberrant transcripts in them. Dystrophin mRNA studies confirmed that 3 predicted DMD missense variants (c.2380G < C, c.4977C < G, and c.5444A < G) were in fact splicing and frameshift variants due to aberrant splicing. The 9 DMD variants were re-interpreted as pathogenic or likely pathogenic based on mRNA and protein studies. Therefore, 3 patients with DMD splicing variants and 6 patients with confirmed DMD missense variants were diagnosed with DMD and BMD, respectively. Conclusion Our study highlights the importance of muscle biopsy and aberrant splicing for clinical and genetic interpretation of uncertain DMD missense variants. Dystrophinopathies DMD Missense variants Aberrant splicing Medicine R Chang Liu verfasserin aut Haiyan Yu verfasserin aut Zhihao Xie verfasserin aut Chengyue Sun verfasserin aut Ying Zhu verfasserin aut Xiaoyu Hu verfasserin aut Li Bai verfasserin aut Luhua Wei verfasserin aut Peng Sun verfasserin aut Yanyu Lu verfasserin aut Yunlong Lu verfasserin aut Yawen Zhao verfasserin aut Wei Zhang verfasserin aut Zhaoxia Wang verfasserin aut Lingchao Meng verfasserin aut Yun Yuan verfasserin aut In Orphanet Journal of Rare Diseases BMC, 2006 19(2024), 1, Seite 13 (DE-627)50900637X (DE-600)2225857-7 17501172 nnns volume:19 year:2024 number:1 pages:13 https://doi.org/10.1186/s13023-024-03128-7 kostenfrei https://doaj.org/article/86acb045fc3d4749a3f4198b0d35e13c kostenfrei https://doi.org/10.1186/s13023-024-03128-7 kostenfrei https://doaj.org/toc/1750-1172 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 19 2024 1 13 |
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10.1186/s13023-024-03128-7 doi (DE-627)DOAJ095651144 (DE-599)DOAJ86acb045fc3d4749a3f4198b0d35e13c DE-627 ger DE-627 rakwb eng Zhiying Xie verfasserin aut Clinical and genetic interpretation of uncertain DMD missense variants: evidence from mRNA and protein studies 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Pathogenic missense variants in the dystrophin (DMD) gene are rarely reported in dystrophinopathies. Most DMD missense variants are of uncertain significance and their pathogenicity interpretation remains complicated. We aimed to investigate whether DMD missense variants would cause aberrant splicing and re-interpret their pathogenicity based on mRNA and protein studies. Methods Nine unrelated patients who had an elevated serum creatine kinase level with or without muscle weakness were enrolled. They underwent a detailed clinical, imaging, and pathological assessment. Routine genetic testing and muscle-derived mRNA and protein studies of dystrophin and sarcoglycan genes were performed in them. Results Three of the 9 patients presented with a Duchenne muscular dystrophy (DMD) phenotype and the remaining 6 patients had a suspected diagnosis of Becker muscular dystrophy (BMD) or sarcoglycanopathy based on their clinical and pathological characteristics. Routine genetic testing detected only 9 predicted DMD missense variants in them, of which 6 were novel and interpreted as uncertain significance. Muscle-derived mRNA studies of sarcoglycan genes didn’t reveal any aberrant transcripts in them. Dystrophin mRNA studies confirmed that 3 predicted DMD missense variants (c.2380G < C, c.4977C < G, and c.5444A < G) were in fact splicing and frameshift variants due to aberrant splicing. The 9 DMD variants were re-interpreted as pathogenic or likely pathogenic based on mRNA and protein studies. Therefore, 3 patients with DMD splicing variants and 6 patients with confirmed DMD missense variants were diagnosed with DMD and BMD, respectively. Conclusion Our study highlights the importance of muscle biopsy and aberrant splicing for clinical and genetic interpretation of uncertain DMD missense variants. Dystrophinopathies DMD Missense variants Aberrant splicing Medicine R Chang Liu verfasserin aut Haiyan Yu verfasserin aut Zhihao Xie verfasserin aut Chengyue Sun verfasserin aut Ying Zhu verfasserin aut Xiaoyu Hu verfasserin aut Li Bai verfasserin aut Luhua Wei verfasserin aut Peng Sun verfasserin aut Yanyu Lu verfasserin aut Yunlong Lu verfasserin aut Yawen Zhao verfasserin aut Wei Zhang verfasserin aut Zhaoxia Wang verfasserin aut Lingchao Meng verfasserin aut Yun Yuan verfasserin aut In Orphanet Journal of Rare Diseases BMC, 2006 19(2024), 1, Seite 13 (DE-627)50900637X (DE-600)2225857-7 17501172 nnns volume:19 year:2024 number:1 pages:13 https://doi.org/10.1186/s13023-024-03128-7 kostenfrei https://doaj.org/article/86acb045fc3d4749a3f4198b0d35e13c kostenfrei https://doi.org/10.1186/s13023-024-03128-7 kostenfrei https://doaj.org/toc/1750-1172 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 19 2024 1 13 |
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10.1186/s13023-024-03128-7 doi (DE-627)DOAJ095651144 (DE-599)DOAJ86acb045fc3d4749a3f4198b0d35e13c DE-627 ger DE-627 rakwb eng Zhiying Xie verfasserin aut Clinical and genetic interpretation of uncertain DMD missense variants: evidence from mRNA and protein studies 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Pathogenic missense variants in the dystrophin (DMD) gene are rarely reported in dystrophinopathies. Most DMD missense variants are of uncertain significance and their pathogenicity interpretation remains complicated. We aimed to investigate whether DMD missense variants would cause aberrant splicing and re-interpret their pathogenicity based on mRNA and protein studies. Methods Nine unrelated patients who had an elevated serum creatine kinase level with or without muscle weakness were enrolled. They underwent a detailed clinical, imaging, and pathological assessment. Routine genetic testing and muscle-derived mRNA and protein studies of dystrophin and sarcoglycan genes were performed in them. Results Three of the 9 patients presented with a Duchenne muscular dystrophy (DMD) phenotype and the remaining 6 patients had a suspected diagnosis of Becker muscular dystrophy (BMD) or sarcoglycanopathy based on their clinical and pathological characteristics. Routine genetic testing detected only 9 predicted DMD missense variants in them, of which 6 were novel and interpreted as uncertain significance. Muscle-derived mRNA studies of sarcoglycan genes didn’t reveal any aberrant transcripts in them. Dystrophin mRNA studies confirmed that 3 predicted DMD missense variants (c.2380G < C, c.4977C < G, and c.5444A < G) were in fact splicing and frameshift variants due to aberrant splicing. The 9 DMD variants were re-interpreted as pathogenic or likely pathogenic based on mRNA and protein studies. Therefore, 3 patients with DMD splicing variants and 6 patients with confirmed DMD missense variants were diagnosed with DMD and BMD, respectively. Conclusion Our study highlights the importance of muscle biopsy and aberrant splicing for clinical and genetic interpretation of uncertain DMD missense variants. Dystrophinopathies DMD Missense variants Aberrant splicing Medicine R Chang Liu verfasserin aut Haiyan Yu verfasserin aut Zhihao Xie verfasserin aut Chengyue Sun verfasserin aut Ying Zhu verfasserin aut Xiaoyu Hu verfasserin aut Li Bai verfasserin aut Luhua Wei verfasserin aut Peng Sun verfasserin aut Yanyu Lu verfasserin aut Yunlong Lu verfasserin aut Yawen Zhao verfasserin aut Wei Zhang verfasserin aut Zhaoxia Wang verfasserin aut Lingchao Meng verfasserin aut Yun Yuan verfasserin aut In Orphanet Journal of Rare Diseases BMC, 2006 19(2024), 1, Seite 13 (DE-627)50900637X (DE-600)2225857-7 17501172 nnns volume:19 year:2024 number:1 pages:13 https://doi.org/10.1186/s13023-024-03128-7 kostenfrei https://doaj.org/article/86acb045fc3d4749a3f4198b0d35e13c kostenfrei https://doi.org/10.1186/s13023-024-03128-7 kostenfrei https://doaj.org/toc/1750-1172 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 19 2024 1 13 |
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10.1186/s13023-024-03128-7 doi (DE-627)DOAJ095651144 (DE-599)DOAJ86acb045fc3d4749a3f4198b0d35e13c DE-627 ger DE-627 rakwb eng Zhiying Xie verfasserin aut Clinical and genetic interpretation of uncertain DMD missense variants: evidence from mRNA and protein studies 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Pathogenic missense variants in the dystrophin (DMD) gene are rarely reported in dystrophinopathies. Most DMD missense variants are of uncertain significance and their pathogenicity interpretation remains complicated. We aimed to investigate whether DMD missense variants would cause aberrant splicing and re-interpret their pathogenicity based on mRNA and protein studies. Methods Nine unrelated patients who had an elevated serum creatine kinase level with or without muscle weakness were enrolled. They underwent a detailed clinical, imaging, and pathological assessment. Routine genetic testing and muscle-derived mRNA and protein studies of dystrophin and sarcoglycan genes were performed in them. Results Three of the 9 patients presented with a Duchenne muscular dystrophy (DMD) phenotype and the remaining 6 patients had a suspected diagnosis of Becker muscular dystrophy (BMD) or sarcoglycanopathy based on their clinical and pathological characteristics. Routine genetic testing detected only 9 predicted DMD missense variants in them, of which 6 were novel and interpreted as uncertain significance. Muscle-derived mRNA studies of sarcoglycan genes didn’t reveal any aberrant transcripts in them. Dystrophin mRNA studies confirmed that 3 predicted DMD missense variants (c.2380G < C, c.4977C < G, and c.5444A < G) were in fact splicing and frameshift variants due to aberrant splicing. The 9 DMD variants were re-interpreted as pathogenic or likely pathogenic based on mRNA and protein studies. Therefore, 3 patients with DMD splicing variants and 6 patients with confirmed DMD missense variants were diagnosed with DMD and BMD, respectively. Conclusion Our study highlights the importance of muscle biopsy and aberrant splicing for clinical and genetic interpretation of uncertain DMD missense variants. Dystrophinopathies DMD Missense variants Aberrant splicing Medicine R Chang Liu verfasserin aut Haiyan Yu verfasserin aut Zhihao Xie verfasserin aut Chengyue Sun verfasserin aut Ying Zhu verfasserin aut Xiaoyu Hu verfasserin aut Li Bai verfasserin aut Luhua Wei verfasserin aut Peng Sun verfasserin aut Yanyu Lu verfasserin aut Yunlong Lu verfasserin aut Yawen Zhao verfasserin aut Wei Zhang verfasserin aut Zhaoxia Wang verfasserin aut Lingchao Meng verfasserin aut Yun Yuan verfasserin aut In Orphanet Journal of Rare Diseases BMC, 2006 19(2024), 1, Seite 13 (DE-627)50900637X (DE-600)2225857-7 17501172 nnns volume:19 year:2024 number:1 pages:13 https://doi.org/10.1186/s13023-024-03128-7 kostenfrei https://doaj.org/article/86acb045fc3d4749a3f4198b0d35e13c kostenfrei https://doi.org/10.1186/s13023-024-03128-7 kostenfrei https://doaj.org/toc/1750-1172 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 19 2024 1 13 |
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10.1186/s13023-024-03128-7 doi (DE-627)DOAJ095651144 (DE-599)DOAJ86acb045fc3d4749a3f4198b0d35e13c DE-627 ger DE-627 rakwb eng Zhiying Xie verfasserin aut Clinical and genetic interpretation of uncertain DMD missense variants: evidence from mRNA and protein studies 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Pathogenic missense variants in the dystrophin (DMD) gene are rarely reported in dystrophinopathies. Most DMD missense variants are of uncertain significance and their pathogenicity interpretation remains complicated. We aimed to investigate whether DMD missense variants would cause aberrant splicing and re-interpret their pathogenicity based on mRNA and protein studies. Methods Nine unrelated patients who had an elevated serum creatine kinase level with or without muscle weakness were enrolled. They underwent a detailed clinical, imaging, and pathological assessment. Routine genetic testing and muscle-derived mRNA and protein studies of dystrophin and sarcoglycan genes were performed in them. Results Three of the 9 patients presented with a Duchenne muscular dystrophy (DMD) phenotype and the remaining 6 patients had a suspected diagnosis of Becker muscular dystrophy (BMD) or sarcoglycanopathy based on their clinical and pathological characteristics. Routine genetic testing detected only 9 predicted DMD missense variants in them, of which 6 were novel and interpreted as uncertain significance. Muscle-derived mRNA studies of sarcoglycan genes didn’t reveal any aberrant transcripts in them. Dystrophin mRNA studies confirmed that 3 predicted DMD missense variants (c.2380G < C, c.4977C < G, and c.5444A < G) were in fact splicing and frameshift variants due to aberrant splicing. The 9 DMD variants were re-interpreted as pathogenic or likely pathogenic based on mRNA and protein studies. Therefore, 3 patients with DMD splicing variants and 6 patients with confirmed DMD missense variants were diagnosed with DMD and BMD, respectively. Conclusion Our study highlights the importance of muscle biopsy and aberrant splicing for clinical and genetic interpretation of uncertain DMD missense variants. Dystrophinopathies DMD Missense variants Aberrant splicing Medicine R Chang Liu verfasserin aut Haiyan Yu verfasserin aut Zhihao Xie verfasserin aut Chengyue Sun verfasserin aut Ying Zhu verfasserin aut Xiaoyu Hu verfasserin aut Li Bai verfasserin aut Luhua Wei verfasserin aut Peng Sun verfasserin aut Yanyu Lu verfasserin aut Yunlong Lu verfasserin aut Yawen Zhao verfasserin aut Wei Zhang verfasserin aut Zhaoxia Wang verfasserin aut Lingchao Meng verfasserin aut Yun Yuan verfasserin aut In Orphanet Journal of Rare Diseases BMC, 2006 19(2024), 1, Seite 13 (DE-627)50900637X (DE-600)2225857-7 17501172 nnns volume:19 year:2024 number:1 pages:13 https://doi.org/10.1186/s13023-024-03128-7 kostenfrei https://doaj.org/article/86acb045fc3d4749a3f4198b0d35e13c kostenfrei https://doi.org/10.1186/s13023-024-03128-7 kostenfrei https://doaj.org/toc/1750-1172 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 19 2024 1 13 |
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Zhiying Xie Chang Liu Haiyan Yu Zhihao Xie Chengyue Sun Ying Zhu Xiaoyu Hu Li Bai Luhua Wei Peng Sun Yanyu Lu Yunlong Lu Yawen Zhao Wei Zhang Zhaoxia Wang Lingchao Meng Yun Yuan |
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Zhiying Xie |
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clinical and genetic interpretation of uncertain dmd missense variants: evidence from mrna and protein studies |
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Clinical and genetic interpretation of uncertain DMD missense variants: evidence from mRNA and protein studies |
abstract |
Abstract Background Pathogenic missense variants in the dystrophin (DMD) gene are rarely reported in dystrophinopathies. Most DMD missense variants are of uncertain significance and their pathogenicity interpretation remains complicated. We aimed to investigate whether DMD missense variants would cause aberrant splicing and re-interpret their pathogenicity based on mRNA and protein studies. Methods Nine unrelated patients who had an elevated serum creatine kinase level with or without muscle weakness were enrolled. They underwent a detailed clinical, imaging, and pathological assessment. Routine genetic testing and muscle-derived mRNA and protein studies of dystrophin and sarcoglycan genes were performed in them. Results Three of the 9 patients presented with a Duchenne muscular dystrophy (DMD) phenotype and the remaining 6 patients had a suspected diagnosis of Becker muscular dystrophy (BMD) or sarcoglycanopathy based on their clinical and pathological characteristics. Routine genetic testing detected only 9 predicted DMD missense variants in them, of which 6 were novel and interpreted as uncertain significance. Muscle-derived mRNA studies of sarcoglycan genes didn’t reveal any aberrant transcripts in them. Dystrophin mRNA studies confirmed that 3 predicted DMD missense variants (c.2380G < C, c.4977C < G, and c.5444A < G) were in fact splicing and frameshift variants due to aberrant splicing. The 9 DMD variants were re-interpreted as pathogenic or likely pathogenic based on mRNA and protein studies. Therefore, 3 patients with DMD splicing variants and 6 patients with confirmed DMD missense variants were diagnosed with DMD and BMD, respectively. Conclusion Our study highlights the importance of muscle biopsy and aberrant splicing for clinical and genetic interpretation of uncertain DMD missense variants. |
abstractGer |
Abstract Background Pathogenic missense variants in the dystrophin (DMD) gene are rarely reported in dystrophinopathies. Most DMD missense variants are of uncertain significance and their pathogenicity interpretation remains complicated. We aimed to investigate whether DMD missense variants would cause aberrant splicing and re-interpret their pathogenicity based on mRNA and protein studies. Methods Nine unrelated patients who had an elevated serum creatine kinase level with or without muscle weakness were enrolled. They underwent a detailed clinical, imaging, and pathological assessment. Routine genetic testing and muscle-derived mRNA and protein studies of dystrophin and sarcoglycan genes were performed in them. Results Three of the 9 patients presented with a Duchenne muscular dystrophy (DMD) phenotype and the remaining 6 patients had a suspected diagnosis of Becker muscular dystrophy (BMD) or sarcoglycanopathy based on their clinical and pathological characteristics. Routine genetic testing detected only 9 predicted DMD missense variants in them, of which 6 were novel and interpreted as uncertain significance. Muscle-derived mRNA studies of sarcoglycan genes didn’t reveal any aberrant transcripts in them. Dystrophin mRNA studies confirmed that 3 predicted DMD missense variants (c.2380G < C, c.4977C < G, and c.5444A < G) were in fact splicing and frameshift variants due to aberrant splicing. The 9 DMD variants were re-interpreted as pathogenic or likely pathogenic based on mRNA and protein studies. Therefore, 3 patients with DMD splicing variants and 6 patients with confirmed DMD missense variants were diagnosed with DMD and BMD, respectively. Conclusion Our study highlights the importance of muscle biopsy and aberrant splicing for clinical and genetic interpretation of uncertain DMD missense variants. |
abstract_unstemmed |
Abstract Background Pathogenic missense variants in the dystrophin (DMD) gene are rarely reported in dystrophinopathies. Most DMD missense variants are of uncertain significance and their pathogenicity interpretation remains complicated. We aimed to investigate whether DMD missense variants would cause aberrant splicing and re-interpret their pathogenicity based on mRNA and protein studies. Methods Nine unrelated patients who had an elevated serum creatine kinase level with or without muscle weakness were enrolled. They underwent a detailed clinical, imaging, and pathological assessment. Routine genetic testing and muscle-derived mRNA and protein studies of dystrophin and sarcoglycan genes were performed in them. Results Three of the 9 patients presented with a Duchenne muscular dystrophy (DMD) phenotype and the remaining 6 patients had a suspected diagnosis of Becker muscular dystrophy (BMD) or sarcoglycanopathy based on their clinical and pathological characteristics. Routine genetic testing detected only 9 predicted DMD missense variants in them, of which 6 were novel and interpreted as uncertain significance. Muscle-derived mRNA studies of sarcoglycan genes didn’t reveal any aberrant transcripts in them. Dystrophin mRNA studies confirmed that 3 predicted DMD missense variants (c.2380G < C, c.4977C < G, and c.5444A < G) were in fact splicing and frameshift variants due to aberrant splicing. The 9 DMD variants were re-interpreted as pathogenic or likely pathogenic based on mRNA and protein studies. Therefore, 3 patients with DMD splicing variants and 6 patients with confirmed DMD missense variants were diagnosed with DMD and BMD, respectively. Conclusion Our study highlights the importance of muscle biopsy and aberrant splicing for clinical and genetic interpretation of uncertain DMD missense variants. |
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Clinical and genetic interpretation of uncertain DMD missense variants: evidence from mRNA and protein studies |
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https://doi.org/10.1186/s13023-024-03128-7 https://doaj.org/article/86acb045fc3d4749a3f4198b0d35e13c https://doaj.org/toc/1750-1172 |
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