ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000021.8) (NC_000021.9)
Evidence for haploinsufficiency phenotype
PubMed ID Description
10508512 Song et al. (1999) identified mutations in RUNX1 in six unrelated families with familial platelet disorder with propensity to develop acute myelogenous leukaemia (FPD/AML), including one intragenic deletion involving at least exons 2-4 (maximum size: exons 2-8) and two nonsensense mutations.
11830488 Michaud et al. (2002) describe three novel mutations in RUNX1 in families with FPD/AML, including a frameshift (R135fsX177) and a nonsense mutation (Y260X).

Haploinsufficiency phenotype comments:

Germline haploinsufficiency of RUNX1 results in familial platelet disorder (FPD); individuals with FPD have an increased risk to eventually develop acute myeloid leukemia (AML). Preudhomme et al. (2009) suggest that a second genetic event in RUNX1 is associated with the development of AML (PMID: 19357396). Of note, constitutional translocations involving this gene are frequently observed in AML. Also of note: There have been several reports of individuals with thrombocytopenia and/or AML and other features, such as developmental delay, due to larger deletions involving RUNX1. For example, Beri-Dexheimer et al. (2008) report a 3.3 Mb deletion involving RUNX1 (and 28 other genes) in an individual with developmental delay, hypotonia, dysmorphic features, and thrombocytopenia. Deletions involving 21q22 are associated with a contiguous gene syndrome known as Braddock-Carey syndrome; this phenotype appears to include thrombocytopenia only if the RUNX1 gene is involved. See PMID: 22614953 for a review of this syndrome.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

Individuals with Trisomy 21 are at increased risk to develop leukemias such as AML. The exact mechanisms by which Trisomy 21 contributes to this risk are unclear. RUNX1 has been one of the genes proposed to play a role in the development of leukemias in individuals with Down syndrome (example: PMID: 19597142), though evidence has also been put forth that it may not play a role (example: PMID: 22221250). The effects of a germline, whole gene duplication of RUNX1 alone are unknown; to date, there has not been a published report describing such individuals.