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The related main theme: A. Stroke and Cerebral vascular disorders



Li-Hsin  Chang,  1, 2 , Chun-Yu  Chen, PhD, MD 2 , Nai-Fang  Chi, PhD, MD 2, 3 , Tsai  Jui-Yao,  2 , Hui-Chi  Huang,  2 , Chun-Jen  Lin, PhD, MD 1, 2 , Chih-Ping  Chung, PhD, MD 2, 3 , Chien-Yi  Tung, PhD 4 , Yo-Tsen  Liu, PhD, MD 1, 2, 3 , I-Hui  Lee, PhD, MD 1, 2, 3 , 
1 Institute of Brain Science, Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
2 Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan
3 Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
4 Genome Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
Corresponding Author:

I-Hui   Lee

keywords: Genetics, Familial stroke, Next-generation sequencing
Abstract for original article

Familial aggregation of stroke is likely attributed to both genetic variants and acquired risk factors which advance the age of onset and increase stroke susceptibility. We investigated the diagnostic yield of rare protein-altering variants which can cause monogenic disorders in a Taiwanese cohort of familial stroke using a whole exome sequencing (WES)-based approach.

We prospectively recruited the stroke patients whose first- or second-degree family members also had stroke by age of 80. The probands were subjected to WES to search potential genetic etiologies except those who had been diagnosed as single gene disorders. Duo- or trio-WES analyses and intra-familial segregation tests by sanger sequencing were performed if the family members are available. The clinical significance of the genetic variant was determined according to 2015 ACMG guideline.

We recruited 140 unrelated probands with familial stroke. 125 had ischemic infarction (89.3%; most common subtype was small vessel disease, n=47), 14 had intracerebral hemorrhage (ICH) (10%), and one had cerebral venous thrombosis-induced hemorrhagic infarction. Single gene analysis identified pathogenic variants in 9 patients (6 NOTCH3, 2 GLA, 1 MELAS). Among the 131 probands with WES analyses, 21 patients (16.1%) were identified having pathogenic/likely pathogenic variants, including NOTCH3 (n=9), ABCC6 (n=2), HTRA1, RNF213, PROS1, JAK2, PKD1, F11, SDHD, F2, and KRIT1. The identification of two novel variants helped greatly in genetic counselling and clinical management of the patients and their family: F2:p.F382L in a family with cerebral venous thrombosis-induced hemorrhagic infarction, and KRIT1:p.E379X in a pedigree of cerebral cavernous malformations complicated with ICH.

Our findings documented monogenic diseases contribute to a significant portion of familial stroke in Taiwanese population, which might be overlooked previously. Our results also supported both the feasibility and necessity of WES-based approach in well-characterized familial stroke patients.