Monogenic Causes in Familial Stroke Across Intracerebral Hemorrhage and Ischemic Stroke Subtypes Identified by Whole-Exome Sequencing

• DOI: 10.1007/s10571-022-01315-3
• Publication Date: 2022-12-29T11:02:42Z
• Authors: Li-Hsin Chang; Nai-Fang Chi; Chun-Yu Chen; Yung-Shuan Lin; Shao-Lun Hsu; Jui-Yao Tsai; Hui-Chi Huang; Chun-Jen Lin; Chih-Ping Chung; Chien-Yi Tung; Chung-Jiuan Jeng; Yi-Chung Lee; Yo-Tsen Liu; I-Hui Lee
• Keywords: Proband; Etiology; Stroke

Whole exome sequencing (WES) has been used to detect rare causative variants in neurological diseases. However, the efficacy of WES genetic diagnosis clinically heterogeneous familial stroke remains inconclusive. We prospectively searched for disease-causing unrelated probands with defined by candidate gene/hotspot screening and/or WES, depending on subtypes and neuroimaging features at a referral center. The clinical significance each variant was determined according American College Medical Genetics guidelines. Among 161 (mean age onset 53.2 ± 13.7 years; male 63.4%), 33 participants (20.5%) had identified 19 pathogenic/likely pathogenic (PVs; applied 152/161 = 94.4%). Across subtypes, highest hit rate (HR) intracerebral hemorrhage (ICH, 7/18 38.9%), particularly etiological subtype structural vasculopathy (4/4 100%, PVs ENG, KRIT1, PKD1, RNF213); followed ischemic small vessel disease (SVD, 15/48 31.3%; NOTCH3, HTRA1, HBB). In contrast, large artery atherosclerosis (LAA, 4/44 9.1%) cardioembolism (0/11 0%) lowest HR. NOTCH3 most common gene (16/161 9.9%), presenting multiple SVD (n 13), ICH 2), or LAA 1). Importantly, we disclosed two previously unreported PVs, KRIT1 p.E379* cerebral cavernous malformation, F2 p.F382L venous sinus thrombosis. contribution monogenic etiologies high our Taiwanese cohort. Utilizing subtype-guided hotspot subsequent unraveled causes 20.5% probands, including 1.2% novel PVs. Genetic may enable early diagnosis, management lifestyle modification. likely related stroke. positive among all (ICH) (SVD). Notably, variants, malformation thrombosis, were disclosed. CVT thrombosis; HTN Hypertensive subtype; atherosclerosis; SV vasculopathy; U Undetermined.