Genetic Insights Into Cryptogenic Stroke: From Etiologic Heterogeneity to Clinical Translation.

Cryptogenic stroke remains challenging because its complex etiology and limited diagnostic tools hinder precise secondary prevention. Growing genetic evidence suggests that cryptogenic stroke may have identifiable genetic architectures that provide additional insights into etiologic classification. In recent years, large-scale genome-wide association studies, multi-omics integration, and other genetic investigations have begun to reveal signals linked to several potential causes, including occult atrial fibrillation and atrial cardiopathy, nonstenotic carotid artery plaque, patent foramen ovale-related paradoxical embolism, monogenic disorders, clonal hematopoiesis of indeterminate potential, and cancer-related thrombosis. These findings suggest a possible shift from exclusion-based diagnosis toward a more mechanism-driven approach. Recent genetic discoveries have enabled preliminary work on predictive models for risk stratification. Emerging genetic tools may also offer promising approaches for etiologic stratification and mechanistic investigation. However, current research in this area remains limited by heterogeneous definitions, modest sample sizes, limited ancestral diversity, and gaps in mechanistic and prognostic evidence. Consequently, clinical translation remains at an early stage. Future research should establish larger and more diverse genomic cohorts with longitudinal phenotyping and advance multidimensional data integration. These efforts may refine etiologic classification and support precision treatment in cryptogenic stroke.