HTRA1-related autosomal dominant cerebral small vessel disease

Abstract

Background Homozygous or compound heterozygous mutations in high temperature requirement serine peptidase A1 ( HTRA1 ) gene are responsible for cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). Recently, increasing evidence has shown that heterozygous HTRA1 mutations are also associated with cerebral small vessel disease (CSVD) with an autosomal dominant pattern of inheritance. This study was aimed to analyze the genetic and clinical characteristics of HTRA1 -related autosomal dominant CSVD. Methods We presented three new Chinese cases of familial CSVD with heterozygous HTRA1 mutations and reviewed all clinical case reports and articles on HTRA1 -related autosomal dominant CSVD included in PUBMED by the end of March 1, 2020. CARASIL probands with genetic diagnosis reported to date were also reviewed. The genetic and clinical characteristics of HTRA1 -related autosomal dominant CSVD were summarized and analyzed by comparing with CARASIL. Results Forty-four HTRA1 -related autosomal dominant CSVD probands and 22 CARASIL probands were included. Compared with typical CARASIL, HTRA1 -related autosomal dominant probands has a higher proportion of vascular risk factors ( P < 0.001), a later onset age ( P < 0.001), and a relatively slower clinical progression. Alopecia and spondylosis can be observed, but less than those in the typical CARASIL. Thirty-five heterozygous mutations in HTRA1 were reported, most of which were missense mutations. Amino acids located close to amino acids 250–300 were most frequently affected, followed by these located near 150∼200. While amino acids 250∼300 were also the most frequently affected region in CARASIL patients, fewer mutations precede the 200th amino acids were detected, especially in the Kazal-type serine protease domain. Conclusions HTRA1 -related autosomal dominant CSVD is present as a mild phenotype of CARASIL. The trend of regional concentration of mutation sites may be related to the concentration of key sites in these regions which are responsible for pathogenesis of HTRA1 -related autosomal dominant CSVD.

Identified novel heterozygous HTRA1 pathogenic variants in Chinese patients with HTRA1-associated dominant cerebral small vessel disease

“…Up to this study, there have been 40 single heterozygous HTRA1 mutations ( Figure 2 ) ( Verdura et al, 2015 ; Ihara, 2016 ; Nozaki et al, 2016 ; Bougea et al, 2017 ; Di Donato et al, 2017 ; Ito et al, 2018 ; Kono et al, 2018 ; Lee et al, 2018 ; Pati and Battisti, 2018 ; Thaler et al, 2018 ; Wu et al, 2018 ; Zhang et al, 2018 ; Favaretto et al, 2019 ; Liu et al, 2020 ; Ohta et al, 2020 ; Oluwole et al, 2020 ; Zhuo et al, 2020 ; Bekircan-Kurt et al, 2021 ; Grigaitė et al, 2021 ; Shang et al, 2021 ; Cao et al, 2022 ). In this study, we collected 95 Chinese CSVD patients and performed genetic analysis in the probands.…”

Novel In-Frame Deletion in HTRA1 Gene, Responsible for Stroke at a Young Age and Dementia—A Case Study

“…We report a novel HTRA1 heterozygous in-frame deletion. To our knowledge, other in-frame deletion of HTRA1 was reported only twice before in the ClinVar database [ 29 ] and medical literature [ 30 ]. Furthermore, p.Glu177del is adjacent to our variant; however, no clinical data were provided and the variant is classified as a variant of uncertain clinical significance.…”

A novel heterozygous HTRA1 mutation in an Asian family with CADASIL‐like disease

“…Studies found that compared with typical CARASIL, patients with CADASIL‐like disease had a later onset age, a higher proportion of vascular risk factors, a lighter and relatively slow clinical progress, and a lower incidence of extraneurological symptoms, such as early‐onset spondylosis and hair loss. 7 , 13 Due to the late‐onset and the high proportion of vascular risk factors, the family history of this disease is often ignored. Therefore, for patients with CSVD with unknown etiology, the HTRA1 gene screening and head magnetic resonance imaging (MRI) imaging should be considered to determine whether it has a clear family history.…”