脊髓性肌萎缩症SMN1基因 2+0基因型携带者的家系研究

doi:10.16288/j.yczz.20-319

遗传 ›› 2021, Vol. 43 ›› Issue (2): 160-168.doi: 10.16288/j.yczz.20-319

脊髓性肌萎缩症SMN1基因 2+0基因型携带者的家系研究

曹延延¹(), 程苗苗¹, 宋昉¹(), 瞿宇晋¹, 白晋丽¹, 金煜炜¹, 王红¹

¹ 首都儿科研究所遗传室,北京 100020

收稿日期:2020-10-17 出版日期:2021-02-16 发布日期:2020-12-24
基金资助:
国家重点研发计划项目(2016YFC0901505);,中国医学科学院医学与健康科技创新工程项目(2016-I2M-1-008);,中国博士后科学基金项目(2018M630108);,国家自然科学基金项目(81500979);北京市自然科学基金项目(5163028)

Familial study of spinal muscular atrophy carriers with SMN1 (2+0) genotype

Yanyan Cao¹(), Miaomiao Cheng¹, Fang Song¹(), Yujin Qu¹, Jinli Bai¹, Hong Wang¹

¹ Department of Medical Genetics, Capital Institute of Pediatrics, Beijing 100020, China

Received:2020-10-17 Online:2021-02-16 Published:2020-12-24
Supported by:
the National Key Research and Development Program of China(2016YFC0901505);CAMS Initiative for Innovative Medicine(2016-I2M-1-008);the China Postdoctoral Science Foundation(2018M630108);National Natural Science Foundation of China(81500979);Beijing Natural Science Foundation(5163028)

摘要/Abstract

摘要：

脊髓性肌萎缩症(spinal muscular atrophy, SMA)是一种儿童时期较为常见的神经肌肉病,属于常染色体隐性遗传。绝大多数SMA由运动神经元存活基因1 (survival motor neuron 1,SMN1)的纯合缺失突变所致。而SMN1的2+0基因型个体作为一种特殊的SMA携带者,给携带者筛查以及家系的遗传咨询带来了巨大的挑战。已有研究表明,g.27134T>G和g.27706_27707delAT多态位点变异对于Ashkenazi犹太人群中的2+0基因型个体具有提示作用。为进一步探究这两个多态位点是否在中国人群也具有特异性,本研究纳入了44例家系成员和204例已知SMN1基因拷贝数的对照样本。44例家系成员来自于9个无关的SMN1基因纯合缺失的SMA家系,先证者双亲之一疑似为2+0基因型携带者。利用多重连接探针扩增(multiplex ligation-dependent probe amplification, MLPA)和短串联重复(short tandem repeat, STR)连锁分析进行基因型的鉴定以及多态位点的筛查,最终通过对家系三代成员或多子女家系两代成员的分析确定了9个家系中的10例个体为2+0基因型携带者,多态位点筛查显示1例携带3拷贝SMN1基因的个体同时存在g.27134T>G和g.27706_27707delAT多态位点的变异。因此,本研究通过对2+0基因型携带者的鉴定,为家系遗传病的诊断提供了精准的遗传咨询。g.27134T>G和g.27706_27707delAT多态位点可能与中国人群2+0基因型个体的关联度较低,尚需寻找中国人群特异的多态位点以提高2+0基因型携带者的检出率。

关键词: 脊髓性肌萎缩, SMN1基因, 2+0基因型, STR连锁分析, 多态位点

Abstract:

Spinal muscular atrophy (SMA) is a common childhood neuromuscular disease inherited in an autosomal recessive pattern. The majority of SMA patients have a homozygous deletion of survival motor neuron 1 (SMN1) gene. As a special SMA carrier, the (2+0) genotype ofSMN1 poses a great challenge for carrier screening and family genetic counseling. A previous study showed that polymorphisms of g.27134 T>G and g.27706_27707delAT had a predictive effect on (2+0) carriers in the Ashkenazi Jewish population. To further explore whether these two polymorphisms are specific to the Chinese population, the present study recruited 44 family members and 204 controls with knownSMN1copy number. These 44 family members were from nine unrelated SMA families withSMN1 homozygous deletion, and one of the proband parents was suspected to be a (2+0) carrier. Multiplex ligation-dependent probe amplification (MLPA) and short tandem repeat (STR) linkage analyses were used to determine the (2+0) genotype and polymorphism screening. Finally, by analyzing theSMN copies and haplotype from three generations of family members and two generations of multi-child families, ten individuals in nine families were confirmed as (2+0) carriers. Moreover, only one individual with three copies ofSMN1 carried the two polymorphisms of g.27134 T>G and g.27706_27707delAT. Therefore, we provided precise genetic counseling for these SMA families after confirming the (2+0) carriers. The association between the polymorphisms of g.27134T>G and g.27706_27707delAT and Chinese (2+0) carriers might be weak. Hence, it is necessary to find specific polymorphisms in the Chinese population to improve the detection rate of (2+0) carriers.

Key words: spinal muscular atrophy, SMN1, (2+0) genotype, STR linkage analysis, polymorphism

曹延延, 程苗苗, 宋昉, 瞿宇晋, 白晋丽, 金煜炜, 王红. 脊髓性肌萎缩症SMN1基因 2+0基因型携带者的家系研究[J]. 遗传, 2021, 43(2): 160-168.

Yanyan Cao, Miaomiao Cheng, Fang Song, Yujin Qu, Jinli Bai, Hong Wang. Familial study of spinal muscular atrophy carriers with SMN1 (2+0) genotype[J]. Hereditas(Beijing), 2021, 43(2): 160-168.

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参考文献 12

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SMN1拷贝数	SMN1基因型	先证者(%)	先证者父亲(%)	先证者母亲(%)	先证者祖父/母(%)	先证者外祖父/母(%)	先证者同胞(%)
0	0+0	9 (100)	0	0	0	0	0
1	1+0	0	6 (66.7)	3 (33.3)	3 (50)	4 (44.4)	0
2	2+0	0	3(33.3)	6 (66.7)	0	0	1 (50)
3	2+1	0	0	0	3 (50)	5 (55.6) ^a	1 (50)
合计	-	9	9	9	6	9	2

家系	I (祖父/祖母或外祖父/外祖母)	II (父亲/母亲)	III (先证者/同胞)
#1	1/3	2/1	0
#2	3/1	1/2	0
#3	1/3	1/2	0
#4	3/1	2/1	0
#5	1/3	1/2	0
#6	1/3	1/2	0
#7	1/3	2/1	0
#8	3/NA	1/2	0/2
#9	NA	1/2	0/3
合计	8	9	9

脊髓性肌萎缩症SMN1基因 2+0基因型携带者的家系研究

Familial study of spinal muscular atrophy carriers with SMN1 (2+0) genotype

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参考文献 12

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多态位点	SMA家系成员(SMN1基因型)				对照组(SMN1拷贝数)
多态位点	0+0	1+0	2+0	2+1	2拷贝 ^a	3拷贝	4拷贝
g.27134T>G	0	0	0	0	0	1 (6.3%)	0
g.27706_27707delAT	0	0	0	0	0	1 (6.3%)	0
筛查例数	9	16	10	9	187	16	1

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