基于脑小血管病队列的单基因遗传性脑小血管病致病基因低频有害变异的研究

万梦瑶; 刘静怡; 朱以诚; 周立新; 倪俊; 彭斌; 姚明

doi:10.12376/j.issn.2097-0501.2022.02.008

基于脑小血管病队列的单基因遗传性脑小血管病致病基因低频有害变异的研究

doi: 10.12376/j.issn.2097-0501.2022.02.008

1.
中国医学科学院北京协和医学院，北京 100730
2.
中国医学科学院北京协和医院放射科，北京 100730
3.
中国医学科学院北京协和医院神经科，北京 100730

基金项目:

“十三五”国家重点研发计划 2016YFC0901004

详细信息

通信作者:
姚明，E-mail: pumchym2011@163.com

中图分类号: R74
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出版历程
- 收稿日期: 2022-03-09
- 录用日期: 2022-03-24
- 网络出版日期: 2022-06-02

Rare Variants of Monogenic Cerebral Small Vessel Diseases -Related Genes: A Study in a Cohort of Patients with Cerebral Small Vessel Diseases

1.
Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
2.
Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
3.
Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China

Funding:

National Key Research and Development Program of China 2016YFC0901004

More Information

Corresponding author: YAO Ming, E-mail: pumchym2011@163.com

摘要

摘要: 目的探讨脑小血管病队列中明确已知的单基因遗传性脑小血管病(CSVD)致病基因的低频有害变异频率，并初步探讨其与临床症状的相关性。方法纳入2017年3月至2022年1月就诊于北京协和医院神经科住院部及门诊的CSVD患者，收集人口学和临床信息，并留取DNA标本送全外显子组测序。首先对单基因CSVD相关致病基因低频变异的分布、人群特征进行描述性分析，并比较单基因CSVD相关致病基因低频变异携带者与非携带者的临床特征差异。结果本研究共纳入292例CSVD患者，51.03%的患者携带任一单基因CSVD相关基因低频有害变异。携带NOTCH3基因的低频变异者最常见，达70例(23.97%)；其次为携带HTRA1基因、COL4A1和/或COL4A2基因低频变异，均为22例(7.53%)。对一级亲属无卒中家族史的散发性CSVD(n=176)亚组进一步分析发现，47.16%的患者携带任一单基因CSVD相关基因低频变异。单基因CSVD相关基因低频变异携带者起病较非携带者早[(58.76±13.71)岁vs.(63.46±13.21)岁, P=0.003]临床表现与非携带者无显著差异。结论中国CSVDs队列中单基因遗传性CSVDs致病基因的低频有害变异携带率高，以NOTCH3基因低频有害变异最常见，其次为HTRA1、COL4A1/COL4A2。对于原因未明的CSVDs患者，即使缺乏明确家族史，也不可忽视遗传因素的筛查。
- 脑小血管病 /
- 单基因遗传 /
- 散发性 /
- 低频变异 /
- NOTCH3 /
- HTRA1
Abstract: Objective This study aimed at describing the frequency of rare variants of monogenic cerebral small vessel diseases (CSVD) in a cohort of patients with CSVD, and to explore its clinical relevance. Methods This study included CSVD patients visiting the Neurology Department of Peking Union Medical College Hospital(PUMCH) from March 2017 to January 2022, collecting their demographic and clinical information and DNA samples for whole-exome sequencing. Descriptive analysis and statistical analysis were conducted exploring the differences between monogenic CSVD-related gene mutation carriers and noncarriers. Results A total of 292 patients were included, 51.03% of whom carried one or more rare variants of monogenic CSVD-related genes. The most common rare low-frequency variants were located in the NOTCH3 gene (70 patients, 23.97%), followed by HTRA1 and COL4A1/COL4A2 (22 patients, 7.53%) respectively. Among the subgroup of patients without a family history of stroke (n=176), the frequency of rare variants was as high as 47.16%. Compared with non-carriers, the carriers were diagnosed at a younger age (58.76±13.71 vs. 63.46±13.21, P=0.003). No difference was found in phenotypes among single-SNP carriers, multiple-SNPs carriers, and noncarriers. Conclusions The frequency of rare mutation of monogenic CSVD-related genes were relatively high in Chinese CSVD cohort. The most common rare variant was within the NOTCH3, followed by HTRA1 and COL4A1/COL4A2 genes. For CSVD patients of unknown causes, genetic screening should not be neglected even if there is not a family history of the disease.
- cerebral small vessel diseases /
- monogenic cerebral small vessel diseases /
- sporadic cerebral small vessel diseases /
- low-frequency mutation /
- NOTCH3 /
- HTRA1
注释:

作者贡献：通信作者确保描述准确、并得到所有作者的同意。万梦瑶参与实施研究过程、统计分析、文章撰写；刘静怡参与统计分析、文章撰写；朱以诚参与研究选题、研究方案设计和数据收集；周立新、倪俊、彭斌参与数据收集；姚明参与研究选题、研究方案设计、实施研究过程、统计分析以及文章撰写修改。

利益冲突：所有作者均声明不存在利益冲突。

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表 1 人口学信息、临床信息及各亚组间临床特点比较

Table 1. Crude distribution and comparison of demographic and clinical characteristics between rare variant carriers and non-carriers

项目	携带者(n=149)		非携带者(n=143)	P^*	P^**	P^***	P^****
项目	单个基因(n=123)	＞1个基因(n=26)	非携带者(n=143)	P^*	P^**	P^***	P^****
年龄(岁，x±s)	59.03±13.67	57.46±14.11	63.46±13.21	0.003	0.597	0.008	0.038
性别/男[n(%)]	75(61.0)	12(46.2)	92(64.3)	0.298	0.164	0.573
血管疾病危险因素——
高血压/有[n(%)]	85(69.1)	9(34.6)	96(67.1)	0.469	0.001	0.731	0.002
糖尿病/有[n(%)]	17(13.8)	3(11.5)	33(23.1)	0.033	0.756	0.054	0.188
高脂血症/有[n(%)]	38(30.9)	10(38.5)	52(36.4)	0.456	0.453	0.348	0.839
冠心病/有[n(%)]	18(14.6)	0	18(12.7)	0.878	/	0.643	0.055
吸烟史/有[n(%)]	45(36.6)	7(26.9)	67(46.9)	0.038	0.348	0.091	0.060
饮酒史/有[n(%)]	47(38.2)	7(26.9)	47(32.9)	0.545	0.277	0.364	0.551
一级亲属卒中史/有[n(%)]	49(39.8)	13(50.0)	41(30.6)	0.032	0.410	0.080	0.056
缺血性卒中史/有[n(%)]	56(45.5)	13(50.0)	60(42.0)	0.455	0.678	0.559	0.448
脑出血史/有[n(%)]	25(20.3)	2(7.7)	17(11.9)	0.137	0.166	0.060	0.534
癫痫发作史/有[n(%)]	2(1.6)	1(3.8)	8(5.6)	0.109	0.440	0.090	0.716
偏头痛史/有[n(%)]	9(7.3)	4(15.4)	10(7.0)	0.584	0.243	0.919	0.155
就诊时症状——
卒中后遗症/有[n(%)]	15(12.2)	3(11.5)	20(14.0)	0.629	0.926	0.667	0.739
认知障碍/有[n(%)]	91(74.0)	20(76.9)	119(83.2)	0.069	0.755	0.066	0.441
步态障碍/有[n(%)]	31(25.2)	9(34.6)	45(31.5)	0.385	0.325	0.260	0.752
情绪障碍/有[n(%)]	56(45.5)	9(34.6)	78(54.5)	0.062	0.308	0.143	0.062
假性球麻痹/有[n(%)]	52(42.3)	8(30.8)	63(44.1)	0.513	0.277	0.771	0.208
排尿障碍/有[n(%)]	43(35.0)	9(34.6)	57(39.9)	0.382	0.973	0.412	0.615
症状数目/有[中位数(IQR^#)]	2(3)	2(2.5)	3(3)	0.065	0.549	0.104	0.172
^#IQR: 四分位距；^对CSVD相关基因低频有害携带者组和非携带者组两组间差异进行显著性检验；^{ }单个CSVD相关基因低频有害携带者组和＞1个CSVD相关基因低频有害携带者组间post hoc分析；^{ * }非携带者和单个CSVD相关基因低频有害携带者组间post hoc分析；^{ * * *}非携带者和＞1个CSVD相关基因低频有害携带者组间post hoc分析

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表 2 292例CSVD患者中单基因CSVD致病基因低频有害变异

Table 2. Rare variants of monogenic CSVD-related genes among the whole cohort

基因	低频有害变异位点(＞1例的例数)
NOTCH3(n=30)	p.R2109W(2)	p.R1100H(3)	p.R544C(5)	p.G172D	c.T4228G
	p.A1927T p.R1837C p.G1689D p.V1652G p.L1518M(11) p.A1450T p.G1347R(4) p.P1226S	p.R1076C p.S931C p.R785C(2) p.H706L p.C617F p.R607C(4) p.R587C(2) p.A564T(2) p.R558C	p.R449C p.C379R p.C318Y p.V237M(8) p.C224F p.C212Y	p.C168S p.G152C p.R141C p.R133C(2) p.R110C p.C108Y(2) p.C76R p.R75Q(2)	c.5914-1G＞A
HTRA1(n=27)	p.A425V p.D320V	p.T293I p.G276A	p.V209L p.N170H	p.R166C p.L11delinsLS(12)	c.472+6C＞A(7) c.972+1G＞A
COL4A1(n=11)	p.P1569L p.P1440R	p.P1227Q p.T1144R(2)	p.V765I p.R666Q	p.P485A p.P123T	c.1382-2-＞T c.1000-5T＞G
COL4A2(n=13)	p.V1578M p.D1562N p.V1486I	p.R1452Q p.R1431C p.V1385fs	p.P1184L p.V1138M p.D1129fs	p.P649S p.G435fs	p.P123L p.V110I
CTSA(n=10)	p.V412M p.A402V	p.V346M(3)	p.M327T(3)	p.I182V	p.L172P
GLA	p.L60F
TREX1(n=11)	p.R217W p.L179P	p.V64I	p.G47S	p.P24A(3)	p.R15S(4)
APP(n=11)	p.E693K p.K687Q(3)	p.V604M p.P484S	p.E380K p.S193G	c.1090+5G＞A c.355+9G＞A	c.2065-8T＞A
ADA2(n=6)	p.G316R p.F313L(3)	p.P151L	p.R127W	p.V77M	p.I51T
GSN(n=19)	p.A742V p.R701Q p.R701W	p.A587G(2) p.V566M p.S512fs	p.K249M p.V220M p.E143K	p.G66R p.R32fs p.P3fs(3)	c.666+1G＞A UTR5(3)
CTC1(n=7)	p.A1025V p.P813L	p.S583N	p.K242fs	p.V188M	p.G131R(2)

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