Analysis Of A Family Of Hereditary Cerebral Small Vessel Disease Caused By Heterozygous HTRA1 Missense Mutation

Objective:The main clinical features of cerebral small vessel disease are stroke and cognitive impairment,and the causes of different patients are different.Lacunar infarction,high white matter signal,enlarged perivascular space,and microbleeds are the main imaging findings.Although a large number of cases are sporadic,there have been many reports that a clear familial single gene mutation may be the cause of the disease.Among them,autosomal dominant cerebral small vessel disease with subcortical infarction and leukoencephalopathy is the most common hereditary cerebral small vessel disease,and its causative gene is NOTCH3 gene.The main purpose of this study was to analyze the members’ clinical data and screen related genes for their pathogenic genes,who was suspected the autosomal dominant cerebral arterial disease with subcortical infarction and leukoencephalopathy,but the gene detection was negative for NOTCH3 mutation,and no biopsy found in the skin biopsy.Methods:The clinical and imaging data of a patient and members of family in the Department of Neurology,the First Hospital of Shanxi Medical University,with a negative diagnosis of NOTCH3 mutation(proband),no granular osmiophilic material(GOM)found in the skin biopsy,clinical diagnosis of autosomal dominant cerebrovascular like disease with subcortical infarction and leukoencephalopathy was collected.To search for possible pathogenic genes,namely candidate genes,the direct sequencing method was used to perform the known hereditary nature of the proband.The single nucleotide polymorphisms of candidate genes in family members were detected by high-throughput multiple polymerase chain reaction.Finally,the pathogenicity was analyzed by biological softwaresuch as PolyPhen2,SIFT and MutationTaster.Results:The clinical data and test results of proband and its family were analyzed,and the following characteristics were found: repeated stroke and progressive cognitive impairment as the main clinical features;the FLAIR images of the proband and the affected family members showed multiple abnormal signals in the bilateral lateral ventricle and bilateral semi-oval centers;the demyelination of the white matter around the bilateral lateral ventricles was consistent with the imaging findings of cerebral small vessel disease;the results of genetic screening indicated that the patient had a missense mutation in HTRA1 gene;the polyPhen2,SIFT and MutationTaster biological software analysis showed that the pathogenicity was possible,subsequent detection of single nucleotide polymorphism suggested that other members of the family also existed the same mutation.Conclusions:This study found a patient with missense mutation in the HTRA1 gene,single nucleotide polymorphism detection indicated that the same mutation also existed in other diseased members of this family.Based on the prediction of gene pathogenicity,the mutation was found to be harmful,so it is speculated that the mutation of HTRA1 gene may lead to autosomal dominant small cerebral vascular disease.