Background: RUNX1-familial platelet disorder with associated myeloid malignancy (RUNX1-FPDMM) is caused by heterozygous germline variants of RUNX1. With the broader application of next-generation sequencing (NGS)-based gene panel analysis in individuals presenting with benign hematologic abnormalities such as thrombocytopenia, pathogenic RUNX1 variants were more frequently identified, independent of a hematologic malignancy. Objective: This study aimed to describe the clinical and genetic characteristics of individuals with pathogenic germline RUNX1 variants, with a particular focus on platelet function and diagnostic challenges. Methods: We retrospectively analyzed 10 individuals from 6 families with genetically confirmed RUNX1-FPDMM. Platelet counts and function were evaluated using light transmission aggregometry (LTA) and flow cytometry (FC). For genetic analysis, NGS-based panel sequencing for inherited platelet disorders, Sanger sequencing, karyotyping, fluorescence in situ hybridization (FISH), and microarray analysis were performed. Results: Platelet counts ranged between 40 and 208 G/L. In all six tested individuals, LTA revealed impaired aggregation in response to collagen, adenosine diphosphate (ADP), and epinephrine. FC analysis identified a pronounced granule secretion defect in three of the eight tested individuals. Disease-causing RUNX1 variants included whole-gene or intragenic deletions, one missense, two not previously reported non-sense variants, and a mosaic RUNX1 loss most probably due to the loss of a derivative chromosome 21. One patient has developed acute myeloid leukemia (AML), and another was diagnosed with RUNX1-FPDMM due to thrombocytopenia onset following T-lymphoblastic lymphoma. Conclusion: RUNX1-FPDMM is a challenging disease due to its associated increased risk for hematologic malignancies, mainly myelodysplastic syndrome (MDS) or AML. Genetic diagnosis in individuals with thrombocytopenia or functional platelet defects of unknown origin is crucial to offer structured surveillance and patient education. Increased risk of bleeding due to qualitative platelet function defects, particularly granule secretion abnormalities, must be considered when managing patients, especially prior to invasive procedures.