Objective To investigate the clinical manifestations,imaging features,molecular genetic characteristics and possible pathogenic mechanisms of hereditary cerebral small vessel disease (CSVD) caused by heterozygous mutation of HtrA serine protease-1 (HTRA1) gene.Methods The clinical data of a Chinese Han family with CSVD carrying a heterozygous mutation of HTRA 1 gene,which came from the Department of Neurology,Henan Provincial People's Hospital in March 2018,were analyzed retrospectively.The clinical and radiographic features were summarized.Several high-throughput whole exon high-throughput sequencing was used to capture the mutation sites and the Sanger sequencing was used to validate the results.The family diagram was drawn and the 3D model construction and mutation function prediction were performed using silico tools.The relevant literature was reviewed and the pathogenesis was explored.Results The pedigree map showed that the family had an autosomal dominant inheritance pattern.Three generations of the family were investigated,and three family members in the same generation suffered from the disease.The first symptom of the proband was diplopia at the age of 39,accompanied by recurrent stroke,cognitive impairment and mood disorders,without alopecia.Head magnetic resonance imaging revealed bilateral diffuse,symmetric lesions,multiple lacunar infarcts,perivascular space,and microbleeds.The elder sister of the proband developed symptoms of left limb weakness at the age of 46,whose other clinical and imaging features were similar to those of the proband.The proband's mother died at the age of 59 due to repeated strokes.Whole exon sequencing indicated heterozygous missense mutation at c.821G＞A locus of HTRA1 gene in the proband and her 4th elder sibling,which was a new pathogenic mutation after consulting several mutation sites of databases.Function prediction suggested pathogenicity.Conclusions The heterozygous mutation of c.821G＞A in HTRA1 gene may lead to autosomal dominant CVSD.This genetic type should be given clinical attention.%目的 研究HtrA丝氨酸蛋白酶1(HTRAl)基因杂合突变致遗传性脑小血管病的临床表型、影像特点、分子遗传学特征及其可能致病机制.方法 对2018年3月河南省人民医院神经内科收治的一个中国汉族携带HTRA1基因杂合突变的脑小血管病家系临床资料进行回顾性分析,并对其家系成员进行调查,总结其临床、影像特点,采用多种高通量测序方法捕获及Sanger测序验证,绘制家系图,进行蛋白3D模型构建、突变功能预测、致病性分析,查阅相关文献,探讨其发病机制.结果 家系图提示该家系呈常染色体显性遗传模式,3代中共3人发病.先证者39岁起病,首发症状为复视,伴随反复卒中样发作、认知能力下降并出现情绪障碍,不伴脱发.头颅MRI提示双侧脑白质弥漫性、对称性病变,多发腔隙性梗死灶、血管周围间隙和微出血.其四姐46岁起病,首发症状为左侧肢体无力,其他临床与影像学特征与先证者类似.先证者母亲因反复卒中于59岁去世.全外显子测序提示先证者及其四姐存在HTRA1基因c.821G＞A位点杂合错义突变,查阅相关数据库未见该突变类型报道,为新致病突变.蛋白功能预测提示其为致病性突变.结论 HTRA1基因c.821G＞A杂合突变可导致常染色体显性遗传性脑小血管病,该遗传类型应引起临床重视.
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