RUNX1

Gene Facts

• HGNC Symbol: RUNX1 (HGNC:10471)
• HGNC Name: RUNX family transcription factor 1
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: AML1, CBFA2
• Alias symbols: PEBP2A2, AMLCR1
• %HI: 0.45
• pLI: 0.29
• LOEUF: 0.63
• Cytoband: 21q22.12
• Genomic Coordinates:

  GRCh37/hg19:	chr21:36160098-36421599
  GRCh38/hg38:	chr21:34787801-35049302

• MANE Select Transcript: NM_001754.5 ENST00000675419.1
• Function: Forms the heterodimeric complex core-binding factor (CBF) with CBFB. RUNX members modulate the transcription of their target genes through recognizing the core consensus binding sequence 5'- TGTGGT-3', or very rarely, 5'-TGCGGT-3', within their regulatory regions via their runt domain, while CBFB is a non-DNA-binding regulatory subunit that allosterically enhances the sequence-specific DNA-binding capacity of RUNX. The heterodimers bind to the core site of a number of enhancers and promoters, in... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-24659
• ClinGen Curation ID: CCID:007794
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 06/14/2023

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

HI Evidence

• PUBMED: PMID: 31723833
  Duployez et. al described a 62-year-old male proband who received a diagnosis of an AML based on a history of mild thrombocytopenia for decades. His 2 children and one grandchild presented with thrombocytopenia with history of easy bruising. ​ A microdeletion of 51 kb in the RUNX1 (exons 3 and 4) was found the patient and in the 2 adult's relative confirming the diagnosis of FPD/AML​.
• PUBMED: PMID: 18478040
  Beri-Dexheimer et al. describe a male proband first brought to attention at the age of 2 due to purpura without history of easy bruising and bleeding. His mother, a woman without any bleeding or physical abnormality, was found to have mild isolated thrombocytopenia​. The child was found to carry an out-of-frame 8 bp heterozygous deletion (c.442_449del) in exon 4 of RUNX1. The effect of the 8 bp deletion at the protein level was predicted with the EMBOSS Transeq software; if translated, the mutated allele would lead to a severely truncated protein (p.Thr148HisfsX9). The out-of-frame deletion is predicted to be a null allele.​
• PUBMED: PMID: 19357396
  Preudhomme et. al describe patient 4/I:1, a child with thrombocytopenia diagnosed at 2 years of age. The patient developed refractory anemia that progressed to AML and was found to have a complete germline deletion of RUNX1. Constitutional karyotype was normal, whereas bone marrow karyotype performed at MDS and AML stages showed an acquired trisomy 21. ​
• PUBMED: PMID: 33616470
  Almanzi et. al describe a family of three affected individuals, all with a strong history of clinical bleeding, Features include epistaxis and easy bruising associated with low platelet counts. Sequencing detected a novel heterozygous CNV deletion of RUNX1 spanning from exons 3–7 in the affected individuals​.

• HI Evidence 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 (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: 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.