The Clinical Features Of Patients With Dominant Cerebral Small Vessel Disease And Heterozygous HTRA1 Mutation

Background: Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy(CARASIL)is a rare hereditary cerebral small vessel disease(CSVD),which was caused by homozygous and compound heterozygous mutations in HTRA1 and was inherited in an autosomal recessive pattern.Recently,heterozygous mutations in HTRA1 were described in patients with autosomal dominant CSVD.Aim: To screen pathogenic variants in Chinese patients with CSVD and to depict the mutation spectrum and clinical features of heterozygous HTRA1 mutation carriers.Methods: A total of 95 Chinese index patients with typical symptoms of CSVD were selected from March 2015 to July 2019.Clinical information,imaging data,and neuropsychological scale were collected.Whole exome sequencing was performed in the probands,followed by Sanger sequencing.Pathogenicity prediction software was applied to evaluate the pathogenicity of identified variants.The mutation spectrum and clinical phenotype of heterozygous HTRA1 mutations patients were analyzed.Results: We detected five different heterozygous HTRA1 mutations in five pedigrees.These pathogenic variants included three known variants(c.543 del T,c.854C>T,c.889G>A)and two novel variants(c.472+1G>A,c.824C>T).Three of them were distributed in exon 4,one in exon 2,and another splicing variant in intron 1.Four out of five probands presented typical features of CARASIL but less severity.The common clinical features included lacunar infarction,cognitive decline,alopecia,lumbago and spondylosis.All of them showed leukoencephalopathy and the main involved cerebral area include periventricular,centrum semiovale,external capsule,temporal poles,frontal lobe,and corpus callosum but with U-fibers spared.Three probands had intracranial microbleeds.Conclusion: We identified five HTRA1 heterozygous mutations including two novel ones,expanding the mutation spectrum of HTRA1 gene.Patients with heterozygous HTRA1 mutations presented with similar but less severe features of CARASIL and an autosomal dominant inherited pattern.