A homozygous HTRA1 mutation was known to be causative for CARASIL42, while evidence was also showed that heterozygous HTRA1 mutation, which might result in an impaired HTRA1 activation cascade or be unable to form stable trimers, is related to autosomal dominant hereditary cerebral small vessel disease with delayed onset43–45. This evidence concerns the gene HTRA1 and cerebral small vessel disease.