Stroke is one of the main causes of death and disability worldwide. Nevertheless, despite the global burden of this disease, our understanding is limited and there is still a lack of highly efficient etiopathology-based treatment. It is partly due to the complexity and heterogenicity of the disease. It is estimated that around one-third of ischemic stroke is heritable, emphasizing the importance of genetic factors identification and targeting for therapeutic purposes. In this review, the authors provide an overview of the current knowledge of stroke genetics and its value in diagnostics, personalized treatment, and prognostication. As the scale of genetic testing increases and the cost decreases, integration of genetic data into clinical practice is inevitable, enabling assessing individual risk, providing personalized prognostic models and identifying new therapeutic targets and biomarkers. Although expanding stroke genetics data provides different diagnostics and treatment perspectives, there are some limitations and challenges to face. One of them is the threat of health disparities as non-European populations are underrepresented in genetic datasets. Finally, a deeper understanding of underlying mechanisms of potential targets is still lacking, delaying the application of novel therapies into routine clinical practice.

Background/Objectives: Overgrowth syndromes (OGSs) are a heterogeneous group of rare conditions marked by excessive growth and variable neurodevelopmental and systemic features. They are broadly classified into generalized overgrowth (GOG) and segmental overgrowth (SOG), which differ in clinical presentation and genetic mechanisms. However, many cases remain genetically unresolved, especially in underrepresented populations. Methods: We analyzed a binational cohort of patients from Poland and Lithuania with suspected OGSs, using detailed clinical evaluation and exome sequencing (ES) from blood-derived DNA. Variants were interpreted using current clinical guidelines, and phenotypes were compared between the GOG and SOG groups. Results: Patients with GOG more often showed developmental delay, intellectual disability, neurological issues, and joint laxity, while vascular malformations were more common in patients with SOG. Dysmorphic features appeared earlier in the SOG group, but became more pronounced over time in the GOG group. Genetic analysis led to the identification of definitive diagnoses in 25% of individuals. Pathogenic variants were identified in the genes involved in chromatin regulation and epigenetic control (DNMT3A, EED, KMT5B, CHD3, and NSD1), along with novel variants expanding the known spectrum. Conclusions: These findings provide valuable insights into the genetic architecture of OGSs in underrepresented Central and North-Eastern European populations, supporting the development of region-specific diagnostic and surveillance strategies.