Pedigrees of investigated patients. Panels A-G display pedigrees of investigated patients. Color-coded triangles above individual symbols refer to their genotypes (NM_001001890.3). Numbers below individuals indicate platelet counts. Arrows indicate index patients. (A) Ser67Arg. Familial leukemia was suspected in a man with MDS because 2 siblings had thrombocytopenia and died of AML. Germline RUNX1:c.201C>G p.(Ser67Arg) was identified in the index, and his daughter had mild thrombocytopenia. At 49 years of age, clonal hematopoiesis was observed in the peripheral blood of the daughter (ie, DNMT3A, NM_022552.4:c.216del p.[Leu723Serfs*56], variant allele frequency [VAF] 32.5%; TP53, NM_000546.4:c.722C>A p.[Ser241Tyr], VAF 12.4%). RUNX1:c.199A>C p.(Ser67Arg) had been previously reported in the RUNX1 Database and was included in our studies. Functional data obtained were applied to classify the patient’s variant. (B) Arg80Ser. The variant was identified in a 19-year-old patient with quantitative and qualitative (ie, storage pool disease) platelet defects, psoriasis, and allergic rhinitis. No hematologic malignancy or additional relatives with platelet defects were reported. (C) Arg205Trp. The index patient had storage pool disease, thrombocytopenia, and developed AML at 26 years of age when RUNX1:c.263C>A p.(Ala88Asn) was identified as an additionally acquired somatic RUNX1 variant. Arg205Trp was inherited from III-2 having qualitative (ie, storage pool disease) but no quantitative platelet defects. Storage pool disease was also known in the maternal grandmother (II-2) whose maternal uncle (I-3) died of AML. (D) Asp96His. This variant was identified in a mother and her daughter reported minor bleeding issues while having normal platelet counts. Functional platelet tests displayed qualitative defects only in I-2. No MDS and/or AML was reported in the family. Whole-exome sequencing in II-1 did not reveal alternative candidate variants, so RUNX1-FPD was diagnosed, but following the MM-VCEP criteria publication, Asp96His was reclassified to VUS. (E) Pro218Ser. The variant was identified in monozygotic twins with thrombocytopenia. RUNX1-FPD was diagnosed.¹⁷  However, the variant was also identified in the twins’ father, who had no quantitative and no qualitative platelet defects. This raised suspicion regarding pathogenicity of the variant. To date, even after an extended thrombocytopenia panel, the genetic origin of the thrombocytopenia remains unknown. (F) Arg223His. The variant was reported as secondary finding by whole-exome sequencing in a 5-year-old girl who, following preterm birth, had developed bronchopulmonary dysplasia with subsequent chronic lung disease, hearing loss, and skeletal dysplasia with infantile scoliosis. Larsen syndrome was diagnosed. No thrombocytopenia or abnormal whole blood cell counts were seen. Functional platelet tests had not been performed. Idiopathic thrombocytopenia was reported for the maternal grandmother; however, her mother did not carry the variant. (G) Arg223His. In this family, the same variant as in family F was identified in a 12-year-old patient with refractory cytopenia in childhood. She was tested for hereditary bone marrow failure while being scheduled for hematopoietic stem cell transplantation (HSCT). na, no genetic testing.