一例X染色体结构重排导致DMD疾病

doi:10.16288/j.yczz.22-179

遗传 ›› 2023, Vol. 45 ›› Issue (1): 88-95.doi: 10.16288/j.yczz.22-179

一例X染色体结构重排导致DMD疾病

胡浩^3,⁴(), 杨晓文^3,⁴, 程德华^3,⁴, 李秀蓉^3,⁴, 何文斌^3,⁴, 胡晓^3,⁴, 高伯笛^3,⁴, 赵晓蒙^3,⁴, 张前军^1,^2,^3,⁴, 杜娟^1,^3,⁴, 刘激扬⁵, 卢光琇^1,^2,^3,⁴, 林戈^1,^2,^3,⁴, 李汶^1,^3,⁴()

1.中南大学基础医学院生殖与干细胞工程研究所，长沙 410078
2.人类干细胞国家工程研究中心，长沙 410078
3.中信湘雅生殖与遗传专科医院，长沙 410000
4.湖南省生殖与遗传临床医学研究中心，长沙 410000
5.长沙市卫生健康委员会，长沙 410023

收稿日期:2022-09-26 修回日期:2022-11-16 出版日期:2023-01-20 发布日期:2022-12-12
通讯作者: 李汶 E-mail:leonhu97@126.com;liwen1968@csu.edu.cn
作者简介:胡浩，副主任医师，研究方向：遗传病的诊断、产前诊断和植入前遗传学检测，遗传咨询。E-mail: leonhu97@126.com
基金资助:
长沙市健康民生项目(遗传性罕见病综合防控);湖南创新型省份建设专项经费(2019SK4012)

A DMD case caused by X chromosome rearrangement

Hao Hu^3,⁴(), Xiaowen Yang^3,⁴, Dehua Cheng^3,⁴, Xiurong Li^3,⁴, Wenbin He^3,⁴, Xiao Hu^3,⁴, Bodi Gao^3,⁴, Xiaomeng Zhao^3,⁴, Qianjun Zhang^1,^2,^3,⁴, Juan Du^1,^3,⁴, Jiyang Liu⁵, Guangxiu Lu^1,^2,^3,⁴, Lin Ge^1,^2,^3,⁴, Wen Li^1,^3,⁴()

1. Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Sciences, Central South University, Changsha 410078, China
2. National Engineering Research Center of Human Stem Cells, Changsha 410078, China
3. CITIC Xiangya Reproductive and Genetic Hospital, Changsha 410078, China
4. Hunan Provincial Clinical Research Center of Reproduction and Genetics, Changsha 410078, China
5. Municipal Health Commission of Changsha, Changsha 410023, China

Received:2022-09-26 Revised:2022-11-16 Online:2023-01-20 Published:2022-12-12
Contact: Li Wen E-mail:leonhu97@126.com;liwen1968@csu.edu.cn
Supported by:
Hunan Innovative Province Construction Special Fund(2019SK4012);the Health and Livelihood Project of Changsha(Comprehensive Prevention);the Health and Livelihood Project of Changsha(Control of Inherited Rare Disorders)

摘要/Abstract

摘要：

假肥大型肌营养不良(Duchenne/Becker muscular dystrophy，DMD/BMD)是一种最常见的进行性肌营养不良疾病，呈X-连锁隐性遗传，主要由DMD基因的缺失、重复及点突变所致，极少数病例是由于染色体结构重排破坏了DMD基因而引起疾病的发生。本文报告了1例经多重连接探针扩增技术(multiplex ligation-dependent probe amplification，MLPA)和下一代测序检测后原因未明的、具有典型症状的DMD患者。采用核型分析、FISH分析及三代测序、Sanger测序综合分析发现，患者存在母源性的X染色体臂间倒位(Chr.X:g. [31939463-31939465del; 31939466-131765063 inv; 131765064-131765067del])半合子变异。由于该变异破坏了DMD基因和HS6ST2基因，因此推测该变异是患者发病的遗传学病因。患者表现肌无力等典型的DMD症状，没有明显的Paganini-Miozzo综合征相关症状。本病例的明确诊断，提示结构重排破坏DMD基因也是导致DMD重要原因之一；常规遗传学检测阴性的患者应考虑核型分析、FISH验证等结构重排变异检测技术，通过三代测序技术能确定大概的重排断点位置，Sanger测序可明确断点区域序列。本病例报告通过明确的遗传学诊断为该患者所在家庭进行生殖干预、降低再生育风险提供了诊疗基础。

关键词: DMD, 结构重排, 核型分析, FISH, 断点分析

Abstract:

Duchenne/Becker muscular dystrophy (DMD/BMD) is one of the most common progressive muscular dystrophy diseases with X-linked recessive inheritance. It is mainly caused by the deletion, duplication and point mutation of DMD gene. In rare cases, it is also caused by the destruction of DMD gene by chromosomal structural rearrangement. Here, we report a case of Duchenne/Becker Muscular dystrophy (DMD/BMD) with typical symptoms but unknown genetic defects after MLPA and next generation sequencing tests in other hospitals. Interestingly, we find a pericentric inversion of X chromosome (Chr.X: g. [31939463-31939465del; 31939466-131765063 inv; 131765064-131765067del]) in this patient. We then use the karyotyping, FISH, long-read sequencing and Sanger sequencing technologies to characterize the chromosome rearrangement. We find that this chromosomal aberration disrupt both the DMD gene and the HS6ST2 gene. The patient present with typical DMD symptoms such as muscle weakness, but no obvious symptoms of Paganini-Miozzo syndrome. Our results suggest that the destruction of DMD gene by structural rearrangement is also one of the important causes of DMD. Therefore, we suggest to provide further genetic testing for those DMD patients with unknown genetic defects through routine genetic testing. Cost-effective karyotyping and FISH should be considered firstly to identify chromosome rearrangements. Long-read sequencing followed by Sanger sequencing could be useful to locate the precise breakpoints. The genetic diagnosis of this case made it possible for reproductive intervention in the patient’s family.

Key words: DMD, structural rearrangement, karyotype, FISH, breakpoint analysis

胡浩, 杨晓文, 程德华, 李秀蓉, 何文斌, 胡晓, 高伯笛, 赵晓蒙, 张前军, 杜娟, 刘激扬, 卢光琇, 林戈, 李汶. 一例X染色体结构重排导致DMD疾病[J]. 遗传, 2023, 45(1): 88-95.

Hao Hu, Xiaowen Yang, Dehua Cheng, Xiurong Li, Wenbin He, Xiao Hu, Bodi Gao, Xiaomeng Zhao, Qianjun Zhang, Juan Du, Jiyang Liu, Guangxiu Lu, Lin Ge, Wen Li. A DMD case caused by X chromosome rearrangement[J]. Hereditas(Beijing), 2023, 45(1): 88-95.

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扩增片段	引物名称	引物序列(5'→3')	片段大小(bp)
1	DMD-F1	GTTTACTTGCTTTCTGCTTGGAT	520
1	HS6ST2-R1	GGGTTGCTTGAGGTAAGGAGT	520
2	DMD-F2	CAATGAGGTAGTAAATGGGAAAT	632
2	HS6ST2-R2	TGTGCCCAATGCTTGTTTC	632
3	DMD-F1	GTTTACTTGCTTTCTGCTTGGAT	570
3	DMD-F2	CAATGAGGTAGTAAATGGGAAAT	570
4	HS6ST2-R1	GGGTTGCTTGAGGTAAGGAGT	587
4	HS6ST2-R1	GGGTTGCTTGAGGTAAGGAGT	587

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一例X染色体结构重排导致DMD疾病

A DMD case caused by X chromosome rearrangement

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