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

Abstract

Biallelic mutations in the high-temperature requirement A serine peptidase 1 (HTRA1) gene are known to cause an extremely rare cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), which belongs to the group of hereditary cerebral small vessel diseases and is mainly observed in the Japanese population. Even though this pathology is inherited in an autosomal recessive manner, recent studies have described symptomatic carriers with heterozygous HTRA1 mutations who have milder symptoms than patients with biallelic HTRA1 mutations. We present the case of a Lithuanian male patient who had a stroke at the age of 36, experienced several transient ischemic attacks, and developed an early onset, progressing dementia. These clinical symptoms were associated with extensive leukoencephalopathy, lacunar infarcts, and microbleeds based on brain magnetic resonance imaging (MRI). A novel heterozygous in-frame HTRA1 gene deletion (NM_002775.5:c.533_535del; NP_002766.1:p.(Lys178del)) was identified by next generation sequencing. The variant was consistent with the patient’s phenotype, which could not be explained by alternative causes, appeared highly deleterious after in silico analysis, and was not reported in the medical literature or population databases to date.

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.…”

Exploring HTRA1-Autosomal Dominant Disease: Literature Review of Clinical Features and Molecular Mechanisms

“…Affected amino acids in HTRA1-autosomal dominant disease are mainly located within the L3/LD loops and the linker region (He et al, 2023;Liu et al, 2020;Uemura et al, 2020). In contrast, CARASIL variants are more dispersed in distribution and spread across the protease domain, with relatively infrequent L3/ LD involvement (Grigaitė et al, 2021). Considering other domains, the Kazal-like region was involved in some cases of HTRA1-autosomal dominant disease but was generally absent in CARASIL patients (Liu et al, 2020;Zhou et al, 2022).…”

Rare c.302C>T TTR Variant Associated with Transthyretin Amyloidosis

“…For the probands from families 1 and 2, next-generation sequencing (NGS) analysis of genomic DNA was performed using TruSightOne Sequencing panels (Illumina Inc., San Diego, CA, USA). For the probands from families 3 and 4, NGS of genomic DNA was performed using Human Core Exome Kits (Twist Bioscience, South San Francisco, California, USA) as previously described [14]. APOA1, APOA2, APOC2, APOC3, B2M, CST3, FGA, GSN, NLRP3 LYZ and TTR genes, associated with amyloidosis, were analyzed.…”