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Abstract Details

Monogenic Diseases in Familial Stroke: A Whole Exome Sequencing-based Study
Cerebrovascular Disease and Interventional Neurology
Cerebrovascular Disease and Interventional Neurology Posters (7:00 AM-5:00 PM)
184

We aim to test the diagnostic yield of monogenic stroke diseases using a whole exome sequencing based approach and explore novel variants in Taiwanese familial stroke. 

Familial aggregation of stroke is likely attributed to clustering of heterogenous heritable and acquired risk factors which increase stroke susceptibility.  WES has enabled cost-effective identification of rare protein-altering variants. 

We consecutively recruited stroke patients whose first- or second-degree family had stroke by age of 80 at a single center between 2016 and 2020. The patients were classified by etiologic subtypes using the TOAST and SMASH-U systems and subjected to WES. Intra-familial segregation was assessed by Sanger validation if available.
Among 133 unrelated probands of familial stroke (89 men and 44 women, age at onset 54.1±14.1 years), 119 had ischemic infarction (89.5%, small vessel disease most common n=45), 13 had hemorrhagic stroke (9.8%) and one had cerebral venous thrombosis-induced hemorrhagic infarction. Except for 9 who had been diagnosed of monogenic stroke diseases, 124 probands were sent to WES. Notably, a likely genetic diagnosis was achieved in 16.9% of the familial stroke patients (n=21, age at onset 54.8 ± 13.2), including 19 patients with known pathogenic/likely pathogenic variants and 2 patients (1.6%) with novel variants considered likely pathogenic. The former included CADASIL (n=9), CADASIL2, Moyamoya disease, factor XI deficiency, protein S deficiency, familial hypercholesterolemia, primary thrombocythemia, polycystic kidney disease with intracranial aneurysm, and pheochromocytoma. For novel variants, we disclosed a patient carrying F2:p.F382L that presented with coagulation factor II deficiency and bilateral hemorrhagic infarction by cerebral venous thrombosis, and the other carrying KRIT1:p.E379X that presented with cerebral cavernous malformation and intracerebral hemorrhage. 

Our findings reveal distinct Taiwanese stroke phenotypes and pathogenic variants, and support the use of WES-based approach in familial stroke patients on the basis of comprehensive clinical and laboratory investigations.
Authors/Disclosures
Li-Hsin Chang, PhD (Taipei Veterans General Hospital)
PRESENTER 		Mr. Chang has nothing to disclose.
No disclosure on file
Chun-Yu Chen, MD, PhD (Taipei Veterans General Hospital) Dr. Chen has nothing to disclose.
No disclosure on file
No disclosure on file
No disclosure on file
No disclosure on file
I-Hui Lee, MD, PhD (Taipei Veterans General Hospital) Dr. Lee has nothing to disclose.