hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

disease
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Also known as asprin-like platelet disorderFamilial Platelet Disorder with Associated Myeloid Malignancyfamilial platelet syndrome with predisposition to acute myelogenous leukaemiafamilial platelet syndrome with predisposition to acute myelogenous leukemiafamilial thrombocytopenia with propensity to acute myelogenous leukaemiafamilial thrombocytopenia with propensity to acute myelogenous leukemiaFPD/AML syndromeFPDMMFPS/AML syndromeplatelet disorder, aspirin-likeplatelet disorder, familial, with associated myeloid malignancythrombocytopenia, familial, with propensity to acute myelogenous leukaemiathrombocytopenia, familial, with propensity to acute myelogenous leukemia

Summary

hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 (MONDO:0100083) is a cancer caused by RUNX1 (GenCC Definitive), with 7 cohort genes (1 CIViC-evidence somatic driver; 1,433 ClinVar predisposition records) and 1 clinical trial.

At a glance

  • Classification: Cancer
  • Causal gene: RUNX1 (GenCC Definitive)
  • Cohort genes: 7
  • ClinVar variants: 1,433
  • Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

FieldValue
Canonical namehereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1
Mondo IDMONDO:0100083
OMIM601399
NCITC151903
UMLSC1832388
MedGen321945
GARD0015329
NORD1943
Is cancer (heuristic)yes

Also known as: asprin-like platelet disorder · Familial Platelet Disorder with Associated Myeloid Malignancy · familial platelet disorder with associated myeloid malignancy · familial platelet syndrome with predisposition to acute myelogenous leukaemia · familial platelet syndrome with predisposition to acute myelogenous leukemia · familial thrombocytopenia with propensity to acute myelogenous leukaemia · familial thrombocytopenia with propensity to acute myelogenous leukemia · FPD/AML syndrome · FPDMM · FPS/AML syndrome · hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 · platelet disorder, aspirin-like · platelet disorder, familial, with associated myeloid malignancy · thrombocytopenia, familial, with propensity to acute myelogenous leukaemia · thrombocytopenia, familial, with propensity to acute myelogenous leukemia

Data availability: 1,433 ClinVar variants · 51 ClinGen variant curations · 5 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary diseasehereditary neoplastic syndromehereditary thrombocytopenia and hematologic cancer predisposition syndromehereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Related subtypes (1): thrombocytopenia 5

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

334 uncertain significance, 193 likely benign, 43 pathogenic, 26 likely pathogenic, 4 benign

ClinVarVariant (HGVS)GeneClassificationReview
1072405NC_000021.8:g.35742772-?_36421202+?delKCNE2Pathogeniccriteria provided, single submitter
1067688NC_000021.8:g.(?36231761)(36231885_?)delRUNX1Pathogeniccriteria provided, single submitter
1068986NM_001754.5(RUNX1):c.713_726del (p.Val238fs)RUNX1Pathogenicreviewed by expert panel
1069299NM_001754.5(RUNX1):c.140_150del (p.Leu47fs)RUNX1Pathogenicreviewed by expert panel
1069843NC_000021.8:g.(?36164426)(36421202_?)delRUNX1Pathogeniccriteria provided, single submitter
1069844NC_000021.8:g.(?36421133)(36421202_?)delRUNX1Pathogeniccriteria provided, single submitter
1071785NM_001754.5(RUNX1):c.777dup (p.Asn260Ter)RUNX1Pathogenicreviewed by expert panel
1073884NM_001754.5(RUNX1):c.601dup (p.Arg201fs)RUNX1Pathogenicreviewed by expert panel
1073907NM_001754.5(RUNX1):c.247dup (p.Ala83fs)RUNX1Pathogenicreviewed by expert panel
1074352NM_001754.5(RUNX1):c.664dup (p.Ser222fs)RUNX1Pathogenicreviewed by expert panel
1074523NM_001754.5(RUNX1):c.528_531dup (p.Thr178fs)RUNX1Pathogenicreviewed by expert panel
1075910NC_000021.8:g.(?36164426)(36171765_?)delRUNX1Pathogeniccriteria provided, single submitter
1076589NM_001754.5(RUNX1):c.149_158dup (p.Ser53fs)RUNX1Pathogenicreviewed by expert panel
1194557NM_001754.5(RUNX1):c.1242C>G (p.Tyr414Ter)RUNX1Pathogenicreviewed by expert panel
1333011Single alleleRUNX1Pathogeniccriteria provided, single submitter
1363605NM_001754.5(RUNX1):c.503del (p.Gly168fs)RUNX1Pathogenicreviewed by expert panel
1438546NM_001754.5(RUNX1):c.585del (p.Thr196fs)RUNX1Pathogenicreviewed by expert panel
14463NM_001754.4(RUNX1):c.352-1G>TRUNX1Pathogenicreviewed by expert panel
14465NM_001754.5(RUNX1):c.328A>G (p.Lys110Glu)RUNX1Pathogenicreviewed by expert panel
14466NM_001754.5(RUNX1):c.508+3delRUNX1Pathogenicreviewed by expert panel
14467NM_001754.5(RUNX1):c.861C>A (p.Tyr287Ter)RUNX1Pathogenicreviewed by expert panel
14468NM_001754.5(RUNX1):c.400G>C (p.Ala134Pro)RUNX1Pathogenicreviewed by expert panel
14470NM_001754.5(RUNX1):c.442_449del (p.Thr148fs)RUNX1Pathogenicreviewed by expert panel
1457966NC_000021.8:g.(?36182049)(36231885_?)delRUNX1Pathogeniccriteria provided, single submitter
1459069NM_001754.5(RUNX1):c.496C>T (p.Arg166Ter)RUNX1Pathogenicreviewed by expert panel
1459404NC_000021.8:g.(?36231761)(36253020_?)delRUNX1Pathogeniccriteria provided, single submitter
1460018NM_001754.5(RUNX1):c.637del (p.Gln213fs)RUNX1Pathogenicreviewed by expert panel
1684407NM_001754.5(RUNX1):c.802C>T (p.Gln268Ter)RUNX1Pathogenicreviewed by expert panel
1684431NM_001754.5(RUNX1):c.566_584dup (p.Thr196fs)RUNX1Pathogenicreviewed by expert panel
1691247NM_001754.5(RUNX1):c.735del (p.Thr246fs)RUNX1Pathogenicreviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

GeneintOGen roleCancer typesCIViC
RUNX1LoFACYC,ALL,AML,BRCA,GBMCIViC #43

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

GeneClassificationInheritanceDiseaseRecords
RUNX1DefinitiveAutosomal dominanthereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX18

Orphanet rare-disease linkage (cohort genes)

GeneOrphanet IDRare disease
RUNX1Orphanet:102724Acute myeloid leukemia with t(8;21)(q22;q22) translocation
RUNX1Orphanet:521Chronic myeloid leukemia
RUNX1Orphanet:71290Familial platelet disorder with associated myeloid malignancy
RUNX1Orphanet:98850Aggressive systemic mastocytosis
KCNE2Orphanet:101016Romano-Ward syndrome
KCNE2Orphanet:334Hereditary atrial fibrillation

Cohort genes → proteins

7 cohort genes, 5 distinct canonical proteins.

Evidence partition

SubsetGenes
multi_evidence7

Cohort genes (full)

SymbolHGNCEnsemblUniProtNameEvidence
RUNX1HGNC:10471ENSG00000159216Q01196Runt-related transcription factor 1gencc,clinvar
CBR1HGNC:1548ENSG00000159228P16152Carbonyl reductase [NADPH] 1clinvar
CLIC6HGNC:2065ENSG00000159212Q96NY7Chloride intracellular channel protein 6clinvar
CBR1-AS1HGNC:55777ENSG00000230212CBR1 antisense RNA 1clinvar
RUNX1-AS1HGNC:56821ENSG00000286153RUNX1 antisense RNA 1clinvar
KCNE2HGNC:6242ENSG00000159197Q9Y6J6Potassium voltage-gated channel subfamily E member 2clinvar
ATP5POHGNC:850ENSG00000241837P48047ATP synthase peripheral stalk subunit OSCP, mitochondrialclinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

SymbolProtein nameFunction (lead sentence)
RUNX1Runt-related transcription factor 1Forms the heterodimeric complex core-binding factor (CBF) with CBFB.
CBR1Carbonyl reductase [NADPH] 1NADPH-dependent reductase with broad substrate specificity.
CLIC6Chloride intracellular channel protein 6In the soluble state, catalyzes glutaredoxin-like thiol disulfide exchange reactions with reduced glutathione as electron donor.
KCNE2Potassium voltage-gated channel subfamily E member 2Ancillary protein that functions as a regulatory subunit of the voltage-gated potassium (Kv) channel complex composed of pore-forming and potassium-conducting alpha subunits and of regulatory beta subunits.
ATP5POATP synthase peripheral stalk subunit OSCP, mitochondrialSubunit OSCP, of the mitochondrial membrane ATP synthase complex (F(1)F(0) ATP synthase or Complex V) that produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of…

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 4 · Druggable fraction: 0.29

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

FamilyGenesFoldFDR
Ion channel115.9×0.244
Enzyme (other)11.7×0.626
Transcription factor11.2×0.626
Other/Unknown41.0×0.626

Per-gene assignment

SymbolFamilyDruggable?ECInterPro (top 3)
RUNX1Transcription factornoAML1_Runt, p53-like_TF_DNA-bd_sf, p53/RUNT-type_TF_DNA-bd_sf
CBR1Enzyme (other)yes1.1.1.184SDR_fam, Sc_DH/Rdtase_CS, NAD(P)-bd_dom_sf
CLIC6Other/UnknownnoCLIC, Glutathione-S-Trfase_C-like, Thioredoxin-like_sf
CBR1-AS1Other/Unknownno
RUNX1-AS1Other/Unknownno
KCNE2Ion channelyesK_chnl_KCNE, K_chnl_volt-dep_bsu_KCNE2
ATP5POOther/UnknownnoATPase_OSCP/dsu, ATPase_OSCP/d_CS, ATP_synth_OSCP/delta_N_sf

Expression context

Cohort genes with no expression data: 0.

6 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

BucketGenes
narrow (1-5 tissues)0
moderate (6-20)0
broad (>20)7
unknown0

Top tissues across cohort

TissueCohort genes
male germ line stem cell (sensu Vertebrata) in testis2
sural nerve2
epithelium of bronchus1
mucosa of paranasal sinus1
olfactory segment of nasal mucosa1
C1 segment of cervical spinal cord1
duodenum1
jejunal mucosa1
bronchial epithelial cell1
bronchus1
pigmented layer of retina1
calcaneal tendon1
bone marrow cell1
body of stomach1
cardia of stomach1
pylorus1
apex of heart1
heart left ventricle1
right atrium auricular region1

Per-gene tissue summary (top 30)

SymbolBgee breadthFANTOM5 breadthSCXATop tissues
RUNX1253ubiquitousmarkerolfactory segment of nasal mucosa, epithelium of bronchus, mucosa of paranasal sinus
CBR1281ubiquitousmarkerjejunal mucosa, duodenum, C1 segment of cervical spinal cord
CLIC6189broadmarkerpigmented layer of retina, bronchial epithelial cell, bronchus
CBR1-AS1126markermale germ line stem cell (sensu Vertebrata) in testis, sural nerve, calcaneal tendon
RUNX1-AS1114markermale germ line stem cell (sensu Vertebrata) in testis, bone marrow cell, sural nerve
KCNE2161tissue_specificyesbody of stomach, pylorus, cardia of stomach
ATP5PO149ubiquitousmarkerheart left ventricle, apex of heart, right atrium auricular region

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

SymbolInteractor count
RUNX14,994
CBR13,942
ATP5PO3,811
CLIC61,246
KCNE2749
CBR1-AS10
RUNX1-AS10

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 2

Cohort genes with PDB structures (top 30)

SymbolUniProtPDB entries
ATP5POP480479
CBR1P161526
RUNX1Q011965
KCNE2Q9Y6J61

AlphaFold-only cohort genes (top 30 by pLDDT)

SymbolUniProtpLDDT
CLIC6Q96NY760.24

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 59. Enrichment computed across 7 evidence-associated genes (4 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

PathwayCohort genesFoldFDRSample cohort genes
RUNX3 regulates RUNX1-mediated transcription1951.7×0.017RUNX1
RUNX1 regulates expression of components of tight junctions1571.0×0.017RUNX1
RUNX1 regulates transcription of genes involved in interleukin signaling1571.0×0.017RUNX1
RUNX2 regulates genes involved in differentiation of myeloid cells1571.0×0.017RUNX1
RUNX1 regulates estrogen receptor mediated transcription1475.8×0.017RUNX1
RUNX1 regulates transcription of genes involved in BCR signaling1475.8×0.017RUNX1
RUNX1 regulates transcription of genes involved in WNT signaling1475.8×0.017RUNX1
RUNX1 regulates transcription of genes involved in differentiation of myeloid cells1356.9×0.017RUNX1
Phase 3 - rapid repolarisation1285.5×0.017KCNE2
RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs)1285.5×0.017RUNX1
RUNX1 regulates transcription of genes involved in differentiation of keratinocytes1285.5×0.017RUNX1
RUNX3 regulates p14-ARF1285.5×0.017RUNX1
Differentiation of naive CD4+ T cells to T helper 1 cells (Th1 cells)1219.6×0.018RUNX1
Synthesis of Prostaglandins (PG) and Thromboxanes (TX)1190.3×0.018CBR1
SLC-mediated transport of organic cations1190.3×0.018RUNX1
R-HSA-5491321190.3×0.018RUNX1
Phase 2 - plateau phase1190.3×0.018KCNE2
Regulation of RUNX1 Expression and Activity1167.9×0.019RUNX1
Formation of ATP by chemiosmotic coupling1142.8×0.021ATP5PO
Arachidonate metabolism1142.8×0.021CBR1
Pre-NOTCH Expression and Processing192.1×0.030RUNX1
Cristae formation186.5×0.031ATP5PO
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known175.1×0.034RUNX1
Transcriptional regulation by RUNX3168.0×0.035RUNX1
SARS-CoV-1 activates/modulates innate immune responses168.0×0.035RUNX1
Transcriptional regulation by RUNX2163.4×0.036RUNX1
R-HSA-425366145.3×0.046RUNX1
Signaling by NOTCH143.9×0.046RUNX1
SARS-CoV-1-host interactions143.9×0.046RUNX1
Mitochondrial biogenesis142.0×0.046ATP5PO

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO termCohort genesFoldFDRSample cohort genes
regulation of connective tissue replacement14213.0×0.007RUNX1
myeloid leukocyte differentiation11404.3×0.007RUNX1
regulation of plasminogen activation11404.3×0.007RUNX1
negative regulation of CD4-positive, alpha-beta T cell differentiation11053.2×0.007RUNX1
cardiac muscle tissue regeneration11053.2×0.007RUNX1
positive regulation of extracellular matrix organization11053.2×0.007RUNX1
positive regulation of CD8-positive, alpha-beta T cell differentiation1842.6×0.007RUNX1
regulation of cardiac muscle cell proliferation1842.6×0.007RUNX1
glucocorticoid metabolic process1702.2×0.007CBR1
positive regulation of granulocyte differentiation1702.2×0.007RUNX1
negative regulation of delayed rectifier potassium channel activity1702.2×0.007KCNE2
prostanoid biosynthetic process1601.9×0.007CBR1
negative regulation of granulocyte differentiation1526.6×0.007RUNX1
vitamin K metabolic process1526.6×0.007CBR1
membrane repolarization during action potential1421.3×0.008KCNE2
membrane repolarization during ventricular cardiac muscle cell action potential1421.3×0.008KCNE2
peripheral nervous system neuron development1383.0×0.008RUNX1
regulation of membrane repolarization1324.1×0.008KCNE2
membrane repolarization1324.1×0.008KCNE2
potassium ion export across plasma membrane1263.3×0.009KCNE2
ATP biosynthetic process1247.8×0.009ATP5PO
ventricular cardiac muscle cell action potential1247.8×0.009KCNE2
positive regulation of proteasomal protein catabolic process1247.8×0.009KCNE2
regulation of ventricular cardiac muscle cell membrane repolarization1210.7×0.010KCNE2
proton motive force-driven ATP synthesis1200.6×0.010ATP5PO
cardiac muscle cell action potential involved in contraction1175.5×0.011KCNE2
myeloid cell differentiation1162.0×0.011RUNX1
positive regulation of collagen biosynthetic process1162.0×0.011RUNX1
hematopoietic stem cell proliferation1162.0×0.011RUNX1
regulation of potassium ion transmembrane transport1156.0×0.011KCNE2

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 5

Druggability breadth: 3 of 7 evidence-associated genes (43%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

SymbolExample approved molecule
RUNX1APOMORPHINE HYDROCHLORIDE
CBR1TRICLOSAN

Top cohort targets by molecule count

SymbolMoleculesMax phase
RUNX124
CBR114
CLIC600
CBR1-AS100
RUNX1-AS100
KCNE200
ATP5PO00

Drugs targeting cohort genes (top 30)

MoleculeMax phaseTargets in cohort
APOMORPHINE HYDROCHLORIDE4RUNX1
TRICLOSAN4CBR1
MOLIBRESIB2RUNX1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

SymbolAssaysType breakdown
CBR135Binding:28, ADMET:7
RUNX120Binding:17, Functional:3
ATP5PO1Binding:1

Cohort enzymes (BRENDA EC)

SymbolEC numbersNames
CBR11.1.1.184carbonyl reductase (NADPH)

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Drug repurposing candidates

3 approved/phased drugs hit cohort targets but don’t yet appear in disease-level clinical trials. Target-inhibition rationale is strongest for cancer driver genes; a bioactivity hit is a screening signal, not a treatment claim.

CompoundMax phaseCohort target (bioactivity)
APOMORPHINE HYDROCHLORIDE4RUNX1
TRICLOSAN4CBR1
MOLIBRESIB2RUNX1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

TierDefinitionGenesSymbols
AApproved (phase 4 drug)2RUNX1, CBR1
BPhased (≥1) drug, not yet approved0
CDruggable family + PDB, no drug1KCNE2
DDruggable family + AlphaFold only, no drug0
EDifficult family or no structure, no drug4CLIC6, CBR1-AS1, RUNX1-AS1, ATP5PO

Undrugged target profiles

5 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

SymbolChEMBL assaysDrugged partners (top 3)
CLIC60
CBR1-AS10
RUNX1-AS10
KCNE20
ATP5PO1

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

PhaseTrials
Not specified1

Top trials by phase / activity

NCTPhaseStatusTitle
NCT03854318Not specifiedRECRUITINGLongitudinal Studies of Patient With FPDMM