Characteristics relevant to RUNX1-, ETV6-, and ANKRD26-driven HPDs
| . | RUNX1 . | ETV6 . | ANKRD26 . |
|---|---|---|---|
| Full gene name | RUNX family transcription factor 1 | ETS variant transcription factor 6 | Ankyrin-repeat domain 26 |
| No. of exons | 9 | 8 | 34 |
| Transcript (HGVS reference) | NM_001754.4 | NM_001987.5 | NM_014915.3 |
| Protein (HGVS reference) | NP_001745.2 | NP_001978.1 | NP_055730.2 |
| Protein length (HGVS reference), amino acids | 480∗ | 452 | 1710 |
| Gene function | Transcription factor: DNA binding, activator, repressor | Transcription factor: DNA binding, repressor | Ankyrin-repeat protein-protein interactions: MAPK/extracellular signal-regulated kinase signaling |
| Disease association | OMIM:601399; MONDO:0011071 | OMIM 616216; MONDO:0014536 | OMIM:188000, MONDO:0008555 |
| First phenotype description | 1969 | Unknown | 1965 |
| First genetic description | 1999 | 2015 | 2011 |
| Mode of inheritance | AD | AD | AD |
| Germ line variants | Missense, nonsense, frameshift, deletions, duplications, splicing, structural variants | Missense, nonsense, frameshift, deletions, structural variants | 5′ UTR variants |
| Disease mechanism | Haploinsufficiency and dominant-negative | Haploinsufficiency and dominant-negative | Loss of RUNX1-, FLI1-, and ETS-binding sites in 5′ UTR, gene derepression |
| Platelet levels, ×109/L | 70-145 | >75 | <150 |
| Platelet function | Aspirin-like defect on platelet aggregometry and α/δ-granule deficits | Normal platelet size and variable mean platelet volume. Abnormal platelet aggregation, α granules deficits | Platelet size is often unchanged |
| Non-HM hematological phenotypes | Thrombocytopenia | Thrombocytopenia | Thrombocytopenia, some reports of red cell macrocytosis, erythrocytosis, neutropenia |
| HMs | MDS, AML, T-cell ALL, T-NHL, CLL, HCL | B-ALL, MPAL, MN, MDS, AML, multiple myeloma, CMML | MDS, AML, CML, CLL |
| HM cumulative risk | 43% by 50 y | 30% | 8% lifetime risk |
| HM median age of onset, y | 29 | 11 | 33 |
| HM age range, y | 2-72 | 2-82 | 1-84 |
| Other phenotypes | Eczema/psoriasis | Not reported | Not available |
| Non-HM malignancies | Breast, prostate, bone, gastric, pancreas, and skin cancer | Melanoma, colorectal, breast, kidney, and skin and meningioma cancer | Prostate, breast, and colon cancer |
| Somatic variant pattern | Loss of RUNX1 WT allele in myeloid. Lymphoid driver variants in lymphoid disease | Hyperdiploid. Loss of ETV6 WT allele | Not well described, add more detail |
| Mouse models and phenotypes | LOF and FPD-MM missense variants/homozygous KO and FPD-MM are embryonic lethal/Runx1R188Q/+ mice: reduced platelet function, defect DNA-damage response, myeloid expansion in the BM | LOF allele, Etv6 P214L knockin mice/KO embryonic lethal/Etv6 P214L homozygous mice: decreased platelet counts, impaired megakaryocyte maturation, and defect in platelet activation | KO allele (not appropriate for disease). No hematological abnormalities |
| . | RUNX1 . | ETV6 . | ANKRD26 . |
|---|---|---|---|
| Full gene name | RUNX family transcription factor 1 | ETS variant transcription factor 6 | Ankyrin-repeat domain 26 |
| No. of exons | 9 | 8 | 34 |
| Transcript (HGVS reference) | NM_001754.4 | NM_001987.5 | NM_014915.3 |
| Protein (HGVS reference) | NP_001745.2 | NP_001978.1 | NP_055730.2 |
| Protein length (HGVS reference), amino acids | 480∗ | 452 | 1710 |
| Gene function | Transcription factor: DNA binding, activator, repressor | Transcription factor: DNA binding, repressor | Ankyrin-repeat protein-protein interactions: MAPK/extracellular signal-regulated kinase signaling |
| Disease association | OMIM:601399; MONDO:0011071 | OMIM 616216; MONDO:0014536 | OMIM:188000, MONDO:0008555 |
| First phenotype description | 1969 | Unknown | 1965 |
| First genetic description | 1999 | 2015 | 2011 |
| Mode of inheritance | AD | AD | AD |
| Germ line variants | Missense, nonsense, frameshift, deletions, duplications, splicing, structural variants | Missense, nonsense, frameshift, deletions, structural variants | 5′ UTR variants |
| Disease mechanism | Haploinsufficiency and dominant-negative | Haploinsufficiency and dominant-negative | Loss of RUNX1-, FLI1-, and ETS-binding sites in 5′ UTR, gene derepression |
| Platelet levels, ×109/L | 70-145 | >75 | <150 |
| Platelet function | Aspirin-like defect on platelet aggregometry and α/δ-granule deficits | Normal platelet size and variable mean platelet volume. Abnormal platelet aggregation, α granules deficits | Platelet size is often unchanged |
| Non-HM hematological phenotypes | Thrombocytopenia | Thrombocytopenia | Thrombocytopenia, some reports of red cell macrocytosis, erythrocytosis, neutropenia |
| HMs | MDS, AML, T-cell ALL, T-NHL, CLL, HCL | B-ALL, MPAL, MN, MDS, AML, multiple myeloma, CMML | MDS, AML, CML, CLL |
| HM cumulative risk | 43% by 50 y | 30% | 8% lifetime risk |
| HM median age of onset, y | 29 | 11 | 33 |
| HM age range, y | 2-72 | 2-82 | 1-84 |
| Other phenotypes | Eczema/psoriasis | Not reported | Not available |
| Non-HM malignancies | Breast, prostate, bone, gastric, pancreas, and skin cancer | Melanoma, colorectal, breast, kidney, and skin and meningioma cancer | Prostate, breast, and colon cancer |
| Somatic variant pattern | Loss of RUNX1 WT allele in myeloid. Lymphoid driver variants in lymphoid disease | Hyperdiploid. Loss of ETV6 WT allele | Not well described, add more detail |
| Mouse models and phenotypes | LOF and FPD-MM missense variants/homozygous KO and FPD-MM are embryonic lethal/Runx1R188Q/+ mice: reduced platelet function, defect DNA-damage response, myeloid expansion in the BM | LOF allele, Etv6 P214L knockin mice/KO embryonic lethal/Etv6 P214L homozygous mice: decreased platelet counts, impaired megakaryocyte maturation, and defect in platelet activation | KO allele (not appropriate for disease). No hematological abnormalities |
AD, autosomal dominant; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; CMML, chronic myelomonocytic leukemia; HCL, hairy cell leukemia; HGVS, Human Genome Variation Society; LOF, loss-of-function; MPAL, mixed phenotype leukemia; T-NHL, T-cell non-Hodgkin lymphoma; WT, wild-type; y, year.
Also known as RUNX1c isoform and is the predominant isoform in hematopoietic cells.