Table 2.

Genes associated primarily with risk for hematopoietic cancer

Gene(s)ConditionHematopoietic cancer(s)Prevalence of hematopoietic cancers36,40 Laboratory featuresOther features
ANKRD26 ANKRD26-related thrombocytopenia AML, CML Unknown Thrombocytopenia None 
BTK X-linked agammaglobulinemia ALL, lymphoma Unknown B-cell deficiency, agammaglobulinemia Recurrent infection 
CBL CBL syndrome JMML <1%  Neurological features 
Noonan syndrome phenotype 
CEBPA Familial AML AML/MDS Unknown  None 
DDX41 Familial AML AML/MDS Unknown  None 
ELANE, HAX1, G6PC3 Congenital neutropenias AML/MDS ∼10% Neutropenia Cardiovascular and/or urogenital abnormalities (G6PC3) 
     Pulmonary hypertension (G6PC3) 
ETV6 Familial leukemia ALL, less commonly MDS/AML, CMML, T/myeloid mixed phenotype leukemia Unknown Thrombocytopenia, red cell macrocytosis None 
FAS, FASLG, CASP10 Autoimmune lymphoproliferative syndrome Lymphoma 8-12% Lymphoproliferation Autoimmune disease 
Autoimmune cytopenias 
GATA2 Familial AML and Emberger syndromes AML/MDS 50% or greater Neutropenia; dendritic cell, monocyte, B-cell and NK cell depletion Primary lymphedema 
Warts 
Deafness 
KLHDC8B Lymphoma predisposition Hodgkin lymphoma Unknown  None 
MPL Congenital amegakaryocytic thrombocytopenia AML/MDS 2% Thrombocytopenia Possibly CNS abnormalities 
Megakaryocytopenia 
Bone marrow failure 
Multiple Severe combined immunodeficiency B-cell lymphoma Unknown Immunodeficiency Failure to thrive 
Recurrent infection 
Autoimmunity 
Short stature 
NPAT Lymphoma predisposition Nodular lymphocyte predominant, Hodgkin lymphoma Unknown  None 
PAX5 Leukemia predisposition ALL Unknown Chromosome 9p loss in leukemia cells None 
RBM8A Thrombocytopenia absent radius syndrome ALL, AML/MDS 1% Thrombocytopenia Absent radii 
Other skeletal anomalies 
Heart defects, genitourinary defects 
Cow’s milk intolerance 
RUNX1 Familial platelet disorder with associated myeloid malignancy AML/MDS, CMML ∼35% Thrombocytopenia None 
SBDS Shwachman-Diamond syndrome ALL, AML/MDS 5-36% Bone marrow failure Pancreatic insufficiency 
Short stature 
Skeletal abnormalities 
SH2B3 Leukemia predisposition ALL Unknown  Growth retardation, developmental delays 
Autoimmune disorders 
SH2D1A X-linked lymphoproliferative disease NHL (B-cell) ∼24% HLH-associated EBV infection Aplastic anemia Vasculitis 
Dysgamma globulinemia 
SRP72 SRP72-associated familial aplasia and myelodysplasia AML Unknown Aplastic anemia Deafness 
Trisomy 21 Down syndrome ALL, AML, TMD 10% (TMD)  Multiple congenital anomalies 
∼2-3% (ALL, AML) Dysmorphic features 
 Intellectual disability 
Unknown Familial monosomy 7 syndrome AML/MDS, ALL Unknown Acquired monosomy 7 None 
Bone marrow failure 
Red cell macrocytosis 
Increased HbF 
WAS WAS-related disorders (including Wiskott-Aldrich syndrome) ALL, lymphoma ∼2% (ALL) Thrombocytopenia neutropenia Eczema 
∼13% (lymphoma) Immunodeficiency Autoimmune disorders 
Gene(s)ConditionHematopoietic cancer(s)Prevalence of hematopoietic cancers36,40 Laboratory featuresOther features
ANKRD26 ANKRD26-related thrombocytopenia AML, CML Unknown Thrombocytopenia None 
BTK X-linked agammaglobulinemia ALL, lymphoma Unknown B-cell deficiency, agammaglobulinemia Recurrent infection 
CBL CBL syndrome JMML <1%  Neurological features 
Noonan syndrome phenotype 
CEBPA Familial AML AML/MDS Unknown  None 
DDX41 Familial AML AML/MDS Unknown  None 
ELANE, HAX1, G6PC3 Congenital neutropenias AML/MDS ∼10% Neutropenia Cardiovascular and/or urogenital abnormalities (G6PC3) 
     Pulmonary hypertension (G6PC3) 
ETV6 Familial leukemia ALL, less commonly MDS/AML, CMML, T/myeloid mixed phenotype leukemia Unknown Thrombocytopenia, red cell macrocytosis None 
FAS, FASLG, CASP10 Autoimmune lymphoproliferative syndrome Lymphoma 8-12% Lymphoproliferation Autoimmune disease 
Autoimmune cytopenias 
GATA2 Familial AML and Emberger syndromes AML/MDS 50% or greater Neutropenia; dendritic cell, monocyte, B-cell and NK cell depletion Primary lymphedema 
Warts 
Deafness 
KLHDC8B Lymphoma predisposition Hodgkin lymphoma Unknown  None 
MPL Congenital amegakaryocytic thrombocytopenia AML/MDS 2% Thrombocytopenia Possibly CNS abnormalities 
Megakaryocytopenia 
Bone marrow failure 
Multiple Severe combined immunodeficiency B-cell lymphoma Unknown Immunodeficiency Failure to thrive 
Recurrent infection 
Autoimmunity 
Short stature 
NPAT Lymphoma predisposition Nodular lymphocyte predominant, Hodgkin lymphoma Unknown  None 
PAX5 Leukemia predisposition ALL Unknown Chromosome 9p loss in leukemia cells None 
RBM8A Thrombocytopenia absent radius syndrome ALL, AML/MDS 1% Thrombocytopenia Absent radii 
Other skeletal anomalies 
Heart defects, genitourinary defects 
Cow’s milk intolerance 
RUNX1 Familial platelet disorder with associated myeloid malignancy AML/MDS, CMML ∼35% Thrombocytopenia None 
SBDS Shwachman-Diamond syndrome ALL, AML/MDS 5-36% Bone marrow failure Pancreatic insufficiency 
Short stature 
Skeletal abnormalities 
SH2B3 Leukemia predisposition ALL Unknown  Growth retardation, developmental delays 
Autoimmune disorders 
SH2D1A X-linked lymphoproliferative disease NHL (B-cell) ∼24% HLH-associated EBV infection Aplastic anemia Vasculitis 
Dysgamma globulinemia 
SRP72 SRP72-associated familial aplasia and myelodysplasia AML Unknown Aplastic anemia Deafness 
Trisomy 21 Down syndrome ALL, AML, TMD 10% (TMD)  Multiple congenital anomalies 
∼2-3% (ALL, AML) Dysmorphic features 
 Intellectual disability 
Unknown Familial monosomy 7 syndrome AML/MDS, ALL Unknown Acquired monosomy 7 None 
Bone marrow failure 
Red cell macrocytosis 
Increased HbF 
WAS WAS-related disorders (including Wiskott-Aldrich syndrome) ALL, lymphoma ∼2% (ALL) Thrombocytopenia neutropenia Eczema 
∼13% (lymphoma) Immunodeficiency Autoimmune disorders 

CML, chronic myeloid leukemia; CNS, central nervous system; HbF, hemoglobin F; HLH, hemophagocytic lymphohistiocytosis.

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