伴有皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病患者临床表型与NOTCH3基因型的关系

目的 探讨伴有皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病（CADASIL）患者NOTCH3基因不同外显子突变与临床表型间的关联。方法 以2015年5月至2017年12月于上海交通大学医学院附属第九人民医院就诊的有临床症状的15个家系30例CADASIL患者作为研究对象，采集患者详细临床资料和基因分析结果，并对患者NOTCH3基因不同外显子突变与发病年龄、首发临床症状、症状性缺血性脑卒中发作次数等临床表型间的关系进行分析。结果 15个家系中共检出NOTCH3基因不同突变位点12个，其中7个位于4号外显子，3个位于11号外显子，另外2个分别位于19号和20号外显子。11号外显子突变的患者发病年龄最晚[（53.6±13.3）岁，n=7]，其次为4号外显子突变的患者[（42.7±5.7）岁，n=15]，而其他外显子（19号和20号）突变的患者发病年龄[（33.5±7.5）岁，n=8]均早于4号和11号外显子突变的患者（P<0.01，P<0.05）。4号外显子突变的患者以运动、语言障碍起病占多数（11/15，73.3%），而19号、20号外显子突变的患者以认知障碍起病多见（7/8，87.5%）。4号外显子突变的患者症状性缺血性脑卒中发作次数中位数为3次，11号外显子突变的患者为2次，而19号、20号外显子突变的患者均未发生症状性缺血性脑卒中。结论 在CADASIL患者中，NOTCH3基因4号和11号外显子为突变热点，不同外显子突变与发病年龄、发病症状和症状性缺血性脑卒中的发生之间存在一定关联。

Relationship between clinical phenotype and NOTCH3 genotype in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Objective To explore the relationship between exon mutations of NOTCH3 gene and clinical phenotype in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).Methods We consecutively included 30 CADASIL patients with clinical symptoms in 15 pedigrees, who visited Shanghai Ninth People''s Hospital, Shanghai Jiao Tong University School of Medicine from May 2015 to Dec. 2017, and collected the clinical data and genetic analysis results. Furthermore, we analyzed the relationship between the exon mutations of NOTCH3 gene and clinical phenotypes, including age at onset, first clinical symptoms and frequency of symptomatic ischemic stroke.Results Twelve mutation sites of NOTCH3 gene were detected in the 15 pedigrees. Seven of them were located in exon 4, 3 in exon 11, 1 in exon 19, and 1 in exon 20. The onset age of the patients carrying exon 11 mutations was the latest ([53.6±13.3] years, n=7), followed by the patients carrying exon 4 mutations ([42.7±5.7] years, n=15). The onset age of 8 patients with mutations in other exons (exon 19 and 20) was (33.5±7.5) years, which was significantly earlier compared with the patients with exon 4 and 11 mutation (P<0.01 and P<0.05). Most of the patients with mutations of exon 4 had motor and speech disorders (11/15, 73.3%), while ones with mutations of exon 19 and 20 had cognitive impairment (7/8, 87.5%). Most of the patients (11/15, 73.3%) carrying mutations in exon 4 had motor and speech disorders at onset, while 7 of 8 patients (87.5%) with mutations in exon 19 and exon 20 had impaired cognition at onset. The times of symptomatic ischemic stroke in patients with mutations in exon 4 was 3 (median) and in patients with mutations in exon 11 was 2 (median), and no symptomatic ischemic stroke occurred in the patients with mutations in exon 19 and 20.Conclusion Exon 4 and exon 11 of NOTCH3 gene are hotspots of mutations in the cohort of CADASIL cases, and the mutations in different exons are associated with onset age, first symptoms and symptomatic ischemic stroke.