Pedigree study of hereditary small cerebral vascular disease caused by c.821G＞A heterozygous mutation of HtrA serine protease-1 gene / 中华神经科杂志

ABSTRACT

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.