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Reclassification of DMD Duplications as Benign: Recommendations for Cautious Interpretation of Variants Identified in Prenatal Screening

Duplications are the main type of dystrophin gene (DMD) variants, which typically cause dystrophinopathies such as Duchenne muscular dystrophy and Becker muscular dystrophy. Maternally inherited exon duplication in DMD in fetuses is a relatively common finding of genetic screening in clinical practi...

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Autores principales: He, Wenbin, Meng, Guiquan, Hu, Xiao, Dai, Jing, Liu, Jiyang, Li, Xiurong, Hu, Hao, Tan, Yueqiu, Zhang, Qianjun, Lu, Guangxiu, Lin, Ge, Du, Juan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9690433/
https://www.ncbi.nlm.nih.gov/pubmed/36360209
http://dx.doi.org/10.3390/genes13111972
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author He, Wenbin
Meng, Guiquan
Hu, Xiao
Dai, Jing
Liu, Jiyang
Li, Xiurong
Hu, Hao
Tan, Yueqiu
Zhang, Qianjun
Lu, Guangxiu
Lin, Ge
Du, Juan
author_facet He, Wenbin
Meng, Guiquan
Hu, Xiao
Dai, Jing
Liu, Jiyang
Li, Xiurong
Hu, Hao
Tan, Yueqiu
Zhang, Qianjun
Lu, Guangxiu
Lin, Ge
Du, Juan
author_sort He, Wenbin
collection PubMed
description Duplications are the main type of dystrophin gene (DMD) variants, which typically cause dystrophinopathies such as Duchenne muscular dystrophy and Becker muscular dystrophy. Maternally inherited exon duplication in DMD in fetuses is a relatively common finding of genetic screening in clinical practice. However, there is no standard strategy for interpretation of the pathogenicity of DMD duplications during prenatal screening, especially for male fetuses, in which maternally inherited pathogenic DMD variants more frequently cause dystrophinopathies. Here, we report three non-contiguous DMD duplications identified in a woman and her male fetus during prenatal screening. Multiplex ligation probe amplification and long-read sequencing were performed on the woman and her family members to verify the presence of DMD duplications. Structural rearrangements in the DMD gene were mapped by long-read sequencing, and the breakpoint junction sequences were validated using Sanger sequencing. The woman and her father carried three non-contiguous DMD duplications. Long-read and Sanger sequencing revealed that the woman’s father carried an intact DMD copy and a complex structural rearrangement of the DMD gene. Therefore, we reclassified these three non-contiguous DMD duplications, one of which is listed as pathogenic, as benign. We postulate that breakpoint analysis should be performed on identified DMD duplication variants, and the pathogenicity of the duplications found during prenatal screening should be interpreted cautiously for clinical prediction and genetic/reproductive counseling.
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spelling pubmed-96904332022-11-25 Reclassification of DMD Duplications as Benign: Recommendations for Cautious Interpretation of Variants Identified in Prenatal Screening He, Wenbin Meng, Guiquan Hu, Xiao Dai, Jing Liu, Jiyang Li, Xiurong Hu, Hao Tan, Yueqiu Zhang, Qianjun Lu, Guangxiu Lin, Ge Du, Juan Genes (Basel) Article Duplications are the main type of dystrophin gene (DMD) variants, which typically cause dystrophinopathies such as Duchenne muscular dystrophy and Becker muscular dystrophy. Maternally inherited exon duplication in DMD in fetuses is a relatively common finding of genetic screening in clinical practice. However, there is no standard strategy for interpretation of the pathogenicity of DMD duplications during prenatal screening, especially for male fetuses, in which maternally inherited pathogenic DMD variants more frequently cause dystrophinopathies. Here, we report three non-contiguous DMD duplications identified in a woman and her male fetus during prenatal screening. Multiplex ligation probe amplification and long-read sequencing were performed on the woman and her family members to verify the presence of DMD duplications. Structural rearrangements in the DMD gene were mapped by long-read sequencing, and the breakpoint junction sequences were validated using Sanger sequencing. The woman and her father carried three non-contiguous DMD duplications. Long-read and Sanger sequencing revealed that the woman’s father carried an intact DMD copy and a complex structural rearrangement of the DMD gene. Therefore, we reclassified these three non-contiguous DMD duplications, one of which is listed as pathogenic, as benign. We postulate that breakpoint analysis should be performed on identified DMD duplication variants, and the pathogenicity of the duplications found during prenatal screening should be interpreted cautiously for clinical prediction and genetic/reproductive counseling. MDPI 2022-10-28 /pmc/articles/PMC9690433/ /pubmed/36360209 http://dx.doi.org/10.3390/genes13111972 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
He, Wenbin
Meng, Guiquan
Hu, Xiao
Dai, Jing
Liu, Jiyang
Li, Xiurong
Hu, Hao
Tan, Yueqiu
Zhang, Qianjun
Lu, Guangxiu
Lin, Ge
Du, Juan
Reclassification of DMD Duplications as Benign: Recommendations for Cautious Interpretation of Variants Identified in Prenatal Screening
title Reclassification of DMD Duplications as Benign: Recommendations for Cautious Interpretation of Variants Identified in Prenatal Screening
title_full Reclassification of DMD Duplications as Benign: Recommendations for Cautious Interpretation of Variants Identified in Prenatal Screening
title_fullStr Reclassification of DMD Duplications as Benign: Recommendations for Cautious Interpretation of Variants Identified in Prenatal Screening
title_full_unstemmed Reclassification of DMD Duplications as Benign: Recommendations for Cautious Interpretation of Variants Identified in Prenatal Screening
title_short Reclassification of DMD Duplications as Benign: Recommendations for Cautious Interpretation of Variants Identified in Prenatal Screening
title_sort reclassification of dmd duplications as benign: recommendations for cautious interpretation of variants identified in prenatal screening
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9690433/
https://www.ncbi.nlm.nih.gov/pubmed/36360209
http://dx.doi.org/10.3390/genes13111972
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