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

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

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。

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 MedicalCollege 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.ResultsA 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 COL4 A1/COL4 A2(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 COL4 A1/COL4 A2 genes.For CSVD patients of unknown causes,genetic screening should not be neglected even if there is not a family history of the disease.