RUNX1 – Familial platelet disorder with associated myeloid malignancy

Familial platelet disorder with associated myeloid malignancy (FPDMM) is an autosomal dominant syndrome caused by germline RUNX1 variants and characterized by lifelong thrombocytopenia and predisposition to hematologic malignancies (PMID:37738626). The RUNX1 gene encodes a core-binding transcription factor essential for definitive hematopoiesis, with evidence from multiple families confirming its role in disease.

Genetic studies across 214 participants from 45 unrelated families demonstrate autosomal dominant inheritance with full penetrance for thrombocytopenia and variable expressivity for malignancy (PMID:37738626). Segregation analysis shows that 44 additional affected relatives carry RUNX1 variants concomitant with disease features. The variant spectrum includes nonsense, frameshift, splice-site, and large exon deletions, indicating haploinsufficiency and dominant-negative mechanisms. A recurrent variant, c.601C>T (p.Arg201Ter), has been reported in FPDMM patients and disrupts the Runt domain integrity (PMID:26021490).

Functional assays support a dominant-negative mechanism for many RUNX1 point mutations. In vitro analyses reveal that Runt domain mutants abolish DNA binding and sequester CBFβ, inhibiting wild-type RUNX1 activity (PMID:11830488). Additionally, transcription activator-like effector nuclease–mediated correction of the c.601C>T mutation in patient-derived iPSCs rescues megakaryopoiesis and platelet maturation, confirming pathogenicity (PMID:26021490).

Mechanistic insights from primary cells and mouse models further corroborate RUNX1 deficiency effects. Heterozygous Runx1-deficient mice and affected human pedigrees show decreased MPL receptor expression and impaired TPO signaling, linking RUNX1 haploinsufficiency to thrombopoietic defects (PMID:15741216). Moreover, natural history studies highlight abnormal platelet dense granule content and dysmegakaryopoiesis preceding malignancy (PMID:37738626).

No significant conflicting evidence disputes this association. Extensive familial, cellular, and animal data collectively establish RUNX1 as a definitive cause of FPDMM. Additional functional studies exceed the ClinGen scoring cap but uniformly support pathogenicity via disrupted transcriptional regulation.

Key Take-home: Germline RUNX1 variants cause an autosomal dominant familial platelet disorder with high penetrance and a leukemia predisposition, guiding genetic testing, surveillance, and risk-adapted management.

References

• Blood • 2002 • In vitro analyses of known and novel RUNX1/AML1 mutations in dominant familial platelet disorder with predisposition to acute myelogenous leukemia: implications for mechanisms of pathogenesis. PMID:11830488
• Experimental hematology • 2015 • Targeted gene correction of RUNX1 in induced pluripotent stem cells derived from familial platelet disorder with propensity to myeloid malignancy restores normal megakaryopoiesis. PMID:26021490
• Blood • 2023 • Natural history study of patients with familial platelet disorder with associated myeloid malignancy. PMID:37738626
• Blood • 2005 • Low Mpl receptor expression in a pedigree with familial platelet disorder with predisposition to acute myelogenous leukemia and a novel AML1 mutation. PMID:15741216

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