腔隙性梗死连续住院患者NOTCH3基因突变分析

Analysis of NOTCH3 gene mutations among 330 consecutive inpatients with lacunar infarction

目的研究腔隙性梗死住院患者NOTCH3基因突变情况。方法纳入2020-10—2021-10广东省中医院脑病中心连续住院的腔隙性梗死患者330例,对所有患者进行NOTCH3基因突变分析,并比较基因突变阳性(CADASIL组)和阴性(非CADASIL组)腔隙性梗死患者的年龄、性别、家族史、血管危险因素、临床和影像表现等。结果330例患者中57例携带NOTCH3基因突变,其中15例为致病性突变(均为c.1630C>T;p.Arg544Cys),总体致病突变率为4.5%(95%CI:2.6%~7.4%)。检测到33种NOTCH3基因突变,包括31种错义突变和2种剪接突变。18例患者存在导致半胱氨酸数量改变的错义突变,总发生率为5.5%(95%CI:3.3%~8.5%)。CADASIL组和非CADASIL组患者年龄、性别、痴呆家族史、血管危险因素、颅内外大动脉狭窄、梗死灶数量、前颞极白质病变、精神障碍、偏头痛比较差异均无统计学意义(P>0.05),脑微出血、脑白质变性、认知障碍差异均有统计学意义(P<0.05)。结论腔隙性梗死患者NOTCH3基因致病性突变率与既往研究结果大致一致,但c.1630C>T突变发生率高于既往估计,在发现有更多的新突变位点前,选择性对突变“热点区域”检测更经济、高效。合并脑微出血、脑白质变性、认知障碍的腔隙性梗死患者的NOTCH3基因筛查更有意义。

Objective To study the NOTCH3 gene mutations in hospitalized patients with lacunar infarction.Methods A total of 330 inpatients with lacunar infarction from October 2020 to October 2021 in Encephalopathy Center,Guangdong Provincial Hospital of Traditional Chinese Medicine were included,and all patients were screened for NOTCH3 gene mutations.The age,gender,family history,vascular risk factors,clinical and imaging manifestations,etc.of patients with positive gene mutations(CADASIL group)and negative(non-CADASIL group)were recorded and compared.Results Among 330 patients,57 patients carried NOTCH3 gene mutations,15 of which were confirmed pathogenic mutations(all c.1630C>T;p.Arg544Cys),with the overall pathogenic mutation frequency of 4.5%(95%CI:2.6%-7.4%).Thirty-three different NOTCH3 gene mutations were detected,including 31 missense mutations and 2 splicing mutations.Missense mutations causing changes in the number of cysteine were found in 18 patients,with an overall incidence of 5.5%(95%CI:3.3%-8.5%).Comparison of the patients with lacunar infarction between the CADASIL group and the non-CADASIL group,there were no statistically significant differences in age,gender,family history of dementia,vascular risk factors,stenosis in the extra or intra-cranial cerebral vessels,number of lacunes,anterior temporal pole white matter lesions,mental disorders,and migraine(P>0.05),the differences in cerebral microbleeds,cerebral white matter degeneration,and cognitive impairment were statistically significant(P<0.05).Conclusion Among hospitalized patients with lacunar infarction,the pathogenic mutation rate of NOTCH3 gene is generally consistent with the results of previous studies,but the c.1630C>T mutation rate is higher than previously estimated.Before more new mutation sites are discovered,it is more cost-effective and efficient to selectively detect mutation“hot spots”.NOTCH3 gene screening is more meaningful for patients with cavity infarction combined with cerebral microbleeds,white matter degeneration,and cognitive impairment.