Xu Sui-Yi, Li Hui-Juan, Li Shun, Ren Qian-Qian, Liang Jian-Lin, Li Chang-Xin
Department of Neurology, Headache Center, The First Hospital of Shanxi Medical University, Taiyuan, People's Republic of China.
Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, People's Republic of China.
Int J Gen Med. 2023 Mar 29;16:1149-1162. doi: 10.2147/IJGM.S404813. eCollection 2023.
High temperature requirement serine peptidase A1 (HTRA1) related cerebral small vessel disease (CSVD) includes both symptomatic heterozygous variant carrier and cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) patients. Presently, most reported symptomatic heterozygous variant carrier cases are sporadic family reports with a lack of specific characteristics. Additionally, the molecular mechanism of heterozygous gene variants is unclear. We conducted this review to collect symptomatic carriers of heterozygous gene variants reported as of 2022, analyzed all pathogenicity according to American College of Medical Genetics and Genomics (ACMG) variant classification, and summarized the cases with pathogenic and likely pathogenic variants gender characteristics, age of onset, geographical distribution, initial symptoms, clinical manifestations, imaging signs, gene variant information and to speculate its underlying pathogenic mechanisms. In this review, we summarized the following characteristics of pathogenic and likely pathogenic symptomatic variant carriers: to date, the majority of reported symptomatic HTRA1 carriers are in European and Asian countries, particularly in China which was found to have the highest number of reported cases. The age of first onset is mostly concentrated in the fourth and fifth decades. The heterozygous gene variants were mostly missense variants. The two variant sites, 166-182 aa and 274-302 aa, were the most concentrated. Clinicians need to pay attention to data and functional data, which may affect the pathogenicity analysis. The decrease in HtrA1 protease activity is currently the most important explanation for the genetic pathogenesis.
高温需求丝氨酸蛋白酶A1（HTRA1）相关的脑小血管病（CSVD）包括有症状的杂合变异携带者和伴有皮质下梗死和白质脑病的脑常染色体隐性动脉病（CARASIL）患者。目前，大多数报道的有症状杂合变异携带者病例为散发性家族报告，缺乏特异性特征。此外，杂合基因变异的分子机制尚不清楚。我们进行本综述以收集截至2022年报道的杂合基因变异有症状携带者，根据美国医学遗传学与基因组学学会（ACMG）变异分类分析所有致病性，并总结具有致病性和可能致病性变异的病例的性别特征、发病年龄、地理分布、初始症状、临床表现、影像学征象、基因变异信息，并推测其潜在致病机制。在本综述中，我们总结了致病性和可能致病性有症状变异携带者的以下特征：迄今为止，大多数报道的有症状HTRA1携带者来自欧洲和亚洲国家，尤其是中国，其报告病例数最多。首次发病年龄大多集中在第四和第五个十年。杂合基因变异大多为错义变异。166 - 182氨基酸和274 - 302氨基酸这两个变异位点最为集中。临床医生需要关注可能影响致病性分析的数据和功能数据。目前，HtrA1蛋白酶活性降低是遗传发病机制的最重要解释。
