Novel mutations in HTRA1 ‐related cerebral small vessel disease and comparison with CADASIL

OBJECTIVE: There is evidence showing both heterozygous HTRA1 and homozygous HTRA1 mutations as causal for familial cerebral small vessel disease (CSVD). The clinical and neuroimaging signs of heterozygous HTRA1‐related CSVD can mimic cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We aimed to characterize the genotypic and phenotypic features of HTRA1‐related CSVD, and we compared the features of heterozygous HTRA1‐related CSVD and CADASIL. METHODS: We carried out genetic sequencing in a series of unrelated patients with suspected familial CSVD from China. Clinical and imaging characteristics of heterozygous HTRA1‐related CSVD and CADASIL were compared. RESULTS: We identified nine heterozygous HTRA1 mutations and one homozygous HTRA1 mutation, seven of which are novel. Compared with CADASIL, patients with heterozygous HTRA1‐related CSVD had a higher proportion of spine disorders and a lower proportion of white matter hyperintensities involving the anterior temporal lobe (p < 0.001). INTERPRETATION: This study shows that most HTRA1‐related CSVD patients in China carry heterozygous HTRA1 mutations. The specific extra‐neurological features and neuroimaging features reveal informative differences between heterozygous HTRA1‐related CSVD and CADASIL. We expand the mutational spectrum of HTRA1.