Table 1.

Common Germline Predispositions in MDS and Acute Leukemias

Gene or Pathway*	Hematologic Malignancy	Additional Hematologic Abnormality	Other Malignancies	Additional Symptoms	Syndrome||	Refs.
CEBPA	AML	No common abnormalities noted	No other malignancies are common	None observed	Familial acute myeloid leukemia with mutated CEBPA	40–42
DDX41	MDS and AML; less commonly lymphoma	Cytopenia	No other malignancies are common	None observed	Familial AML with mutated DDX41	14,63,64
ETV6	ALL, MDS, AML	Thrombocytopenia and decreased platelet function	No other malignancies are common	None observed	Thrombocytopenia 5 (OMIM 616216)	144,145,215
GATA2	MDS and AML	Immunodeficiency, bone marrow failure, monocytopenia and B cell lymphopenia	No other malignancies are common	Lymphedema, pulmonary alveolar proteinosis and congenital deafness	Emberger Syndrome (OMIM 614038) and MonoMac Syndrome (OMIM 614172)	46,245,246
IKZF1	B-ALL, less commonly T-ALL	Immunodeficiency	No other malignancies are common	Autoimmunity	Not described	8,206,207
PAX5	B-ALL	No common abnormalities noted	No other malignancies are common	None observed	Not described	12,166,178
RAS–MAPK pathway: CBL, NF1 and PTPN11	JMML, ALL, AML	JMML-like proliferation with spontaneous regression	Neurofibroma and embryonal rhabdomyosarcoma	Cardiac abnormalities, skin manifestations, growth retardation and facial dysmorphologies	Noonan Syndrome (OMIM 163950); NF1 (OMIM 162200) and other RASopathies	100;95,104;215
RUNX1	MDS and AML, less commonly T-ALL	Thrombocytopenia and decreased platelet function	No other malignancies are common	None observed	Familial platelet disorder with propensity for myeloid malignancy (OMIM 601399)	30,33,36
SAMD9	MDS and AML with monosomy 7	Bone marrow failure	No other malignancies are common	Normophosphatemic familiar tumoral calcinosis; congenital adrenal hypoplasia, enteropathy and genital abnormalities	MIRAGE Syndrome (OMIM 617053) and Myelodysplasia and Leukemia Syndrome with Monosomy 7(OMIM 252270)	16,17,71
SAMD9L	MDS and AML with monosomy 7	Systemic autoinflammatory disease and bone marrow failure	No other malignancies are common	Ataxia	Ataxia Pancytopenia Syndrome (OMIM 159550) and Myelodysplasia and Leukemia Syndrome with Monosomy 7 (OMIM 252270)	18,19,70
TP53	Low hypodiploid ALL, Therapy Related Myeloid Neoplasm	No common abnormalities noted	Osteosarcoma, breast cancer, soft tissue sarcoma, brain tumors and adrenocortical carcinoma	None observed	Li-Fraumeni syndrome (OMIM 151623)	143,150,181
Trisomy 21	AML and ALL	Transient abnormal myelopoiesis	No other malignancies are common	Mental retardation, cardiac abnormalities and facial dysmorphologies	Down syndrome (OMIM 190685)	135

^*Only the major genes and pathways discussed in this Review are included in this table.

^||Online Mendelian Inheritance in Man (OMIM) numbers are given for each syndrome, when applicable: https://www.omim.org/