Monogenic basis of young-onset cryptogenic stroke: a multicenter study

Wei-Zhuang Yuan; Liang Shang; Dai-Shi Tian; Shi-Wen Wu; Yong You; Cheng-Lin Tian; Bo Wu; Jun Liu; Qin-Jian Sun; Qing Liu; Wei-Hai Xu

doi:10.21037/atm-21-3843

Monogenic basis of young-onset cryptogenic stroke: a multicenter study

Ann Transl Med. 2022 May;10(9):512. doi: 10.21037/atm-21-3843.

Authors

Wei-Zhuang Yuan^#¹, Liang Shang^#², Dai-Shi Tian³, Shi-Wen Wu⁴, Yong You⁵, Cheng-Lin Tian⁶, Bo Wu⁷, Jun Liu⁸, Qin-Jian Sun⁹, Qing Liu¹, Wei-Hai Xu¹

Affiliations

¹ 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.
² Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, China.
³ Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁴ Department of Neurology, The Third Medical Center of General Hospital of the Chinese People's Armed Police Force, Beijing, China.
⁵ Department of Neurology, The First Affiliated Hospital of University of South China, Hengyang, China.
⁶ Department of Neurology, Chinese PLA General Hospital, Beijing, China.
⁷ Department of Neurology, West China Hospital, Sichuan University, Chengdu, China.
⁸ Department of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
⁹ Department of Neurology, Shandong Provincial Hospital, Jinan, China.

^# Contributed equally.

Abstract

Background: The prevalence of stroke in young adults is increasing. We investigated the monogenic basis of young adult cryptogenic stroke patients.

Methods: 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.

Results: 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 (NOTCH3), protein kinase AMP-activated noncatalytic subunit gamma 2 (PRKAG2), and ryanodine receptor 2 (RYR2). 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.

Conclusions: 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.

Keywords: Stroke in young adults; genetic; ischemic stroke.