Genotype–Phenotype Spectrum of Overgrowth Syndromes in Polish and Lithuanian Cohorts

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.