Inherited thrombocytopenia results in low platelet counts and increased bleeding. Subsets of these patients have monoallelic germline mutations in either ETV6 or RUNX1 and thus a heightened risk of developing hematologic malignancies. Patients with mutations in either of these transcription factors display the same phenotype of small megakaryocytes that give rise to fewer, less-functional platelets. Utilizing CRISPR/Cas9 technology, we compared and contrasted the in vitro phenotype of hematopoietic progenitor cells and megakaryocytes derived from induced pluripotent stem cell (iPSC) lines harboring mutations in either ETV6 or RUNX1. Both mutant lines display phenotypes consistent with a platelet-related bleeding disorder. Surprisingly, these cellular phenotypes were distinct, suggesting that the mechanisms driving the thrombocytopenia are different. The iPSCs harboring a mutation in ETV6 yield significantly more hematopoietic progenitor cells and megakaryocytes, but the megakaryocytes are immature and less responsive to agonist stimulation. On the contrary, iPSCs with a heterozygous mutation in RUNX1 yield significantly fewer hematopoietic progenitor cells and megakaryocytes, but the megakaryocytes are more responsive to agonist stimulation, though both mutant-MK populations have deficient proplatelet formation. Our work highlights that while patients harboring germline ETV6 or RUNX1 mutations have similar clinical phenotypes, the mechanisms by which these occurs are distinct. This work emphasizes the importance of defining the exact nature of a mutation in patients with a phenotypically similar disorder, as the disease pathology and therapeutic interventions may be different.