Yuan Wei-Zhuang, Shang Liang, Tian Dai-Shi, Wu Shi-Wen, You Yong, Tian Cheng-Lin, Wu Bo, Liu Jun, Sun Qin-Jian, Liu Qing, Xu Wei-Hai
Department of Neurology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, China.
Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, China.
Ann Transl Med. 2022 May;10(9):512. doi: 10.21037/atm-21-3843.
The prevalence of stroke in young adults is increasing. We investigated the monogenic basis of young adult cryptogenic stroke patients.
This multicenter study enrolled cryptogenic stroke patients under 55 years old, and individuals with nonstroke diseases were included as controls. Targeted next-generation sequencing (NGS) was applied with a custom-designed gene panel that included 551 genes. Rare variants were classified into 2 groups: pathogenic variants and variants of unknown significance.
A total of 153 individuals, including 30 (21 males, 70%; mean age 36.1±10.2 years) in the disease group and 123 (59 males, 48.0%; mean age 40.4±13.1 years) in the control group, were recruited. In the disease group, 32 rare variants were identified. Among these individuals, 18 pathogenic variants in 16 patients were detected, with a 53.3% (16/30) diagnostic yield of monogenic causes for cryptogenic stroke. None of these mutations were observed in the control group. Among the mutant genes, the most prevalent were Notch receptor 3 (), protein kinase AMP-activated noncatalytic subunit gamma 2 (), and ryanodine receptor 2 (). Genes associated with cardiogenic diseases showed the highest mutation frequency (10/18, 55.6%) followed by genes associated with small-vessel diseases (SVDs) and coagulation disorders. None of the patients with mutations had evident abnormalities in the heart or other systems checked by routine tests. For the imaging phenotype-genotype association analysis, infarctions in both the anterior and posterior cerebral circulation were only observed in patients with genes related to cardiogenic disease.
In this study, pathogenic variants were identified in nearly half of the young-onset cryptogenic stroke patients, with genes related to cardiogenic diseases being the most frequently mutated. This may have implications for future clinical decision-making, including the development of finer and more sensitive examinations.
年轻成年人中风的患病率正在上升。我们调查了年轻成年隐源性中风患者的单基因基础。
这项多中心研究纳入了55岁以下的隐源性中风患者，并纳入患有非中风疾病的个体作为对照。使用包含551个基因的定制基因面板进行靶向二代测序（NGS）。罕见变异被分为两组：致病变异和意义未明的变异。
共招募了153名个体，包括疾病组的30名（21名男性，70%；平均年龄36.1±10.2岁）和对照组的123名（59名男性，48.0%；平均年龄40.4±13.1岁）。在疾病组中，鉴定出32个罕见变异。在这些个体中，检测到16例患者的18个致病变异，隐源性中风单基因病因的诊断率为53.3%（16/30）。对照组未观察到这些突变。在突变基因中，最常见的是Notch受体3、蛋白激酶AMP激活的非催化亚基γ2和雷诺丁受体2。与心源性疾病相关的基因显示出最高的突变频率（10/18，55.6%），其次是与小血管疾病（SVDs）和凝血障碍相关的基因。所有突变患者经常规检查在心脏或其他系统均无明显异常。对于影像学表型-基因型关联分析，仅在与心源性疾病相关基因的患者中观察到大脑前循环和后循环梗死。
在本研究中，近一半的年轻起病隐源性中风患者中鉴定出致病变异，与心源性疾病相关的基因是最常发生突变的。这可能对未来的临床决策有影响，包括开发更精细、更敏感的检查。
