Report of two pedigrees with heterozygous HTRA1 variants-related cerebral small vessel disease and literature review

Abstract

Background: Biallelic HTRA1 pathogenic variants are associated with autosomal recessive cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). Recent studies have indicated that heterozygous HTRA1 variants are related to autosomal dominant hereditary cerebral small vessel disease (CSVD). However, few studies have assessed heterozygous HTRA1 carriers or the genotype-phenotype correlation.

Methods: The clinical data of two unrelated Chinese Han families with CSVD were collected. Panel sequencing was used to search for pathogenic genes, Sanger sequencing was used for verification, three-dimensional protein models were constructed, and pathogenicity was analyzed. Published HTRA1-related phenotypes included in PubMed up to September 2021 were extensively reviewed, and the patients' genetic and clinical characteristics were summarized.

Results: We report a novel heterozygous variant c.920T>C p.L307P in the HTRA1, whose main clinical and neuroimaging phenotypes are stroke and gait disturbance. We report another patient with the previously reported pathogenic variant HTRA1 c.589C>T p.R197X characterized by early cognitive decline. A literature review indicated that compared with CARASIL, HTRA1-related autosomal dominant hereditary CSVD has a later onset age, milder clinical symptoms, fewer extraneurological symptoms, and slower progression, indicating a milder CARASIL phenotype. In addition, HTRA1 heterozygous variants were related to a higher proportion of vascular risk factors (p < .001) and male sex (p = .022).

Conclusion: These findings broaden the known mutational spectrum and possible clinical phenotype of HTRA1. Considering the semidominant characteristics of HTRA1-related phenotypes, we recommend that all members of HTRA1 variant families undergo genetic screening and clinical follow-up if carrying pathogenic variants.

Keywords: Alzheimer's disease; CARASIL; HTRA1; cerebral small vessel disease; heterozygous variant.