Germ line mutations associated with leukemia
| Predisposition . | Inheritance . | Genes . | Altered pathway/function . | Hematologic malignancies . |
|---|---|---|---|---|
| Syndromic predispositions to leukemia | ||||
| FA | AR, XLR | FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, FANCM, and FANCT; | DNA damage/repair | MDS, AML |
| FANCI and FANCD2; | ||||
| BRCA2/FANCD1, BRCA1/FANCS, FANCR/RAD51, FANCJ, FANCN, FANCO, FANCP, and FANCQ | ||||
| Dyskeratosis congenita | AD, AR, XLR | DKC1, TERC, and TINF2 | Telomere maintenance | MDS, AML |
| TERT, NHP2, NOP10, WRAP53, RTEL1, CTC1, PARN | ||||
| Down syndrome | Sporadic | Unknown | Multifactorial | AMKL, ALL |
| RASopathies | AD | NF1, PTPN11, KRAS, NRAS, SOS1, RAF1, CBL, SHOC2, HRAS, BRAF, MEK1, MEK2, and SPRED1 | RAS signaling | NS-MPD, JMML |
| GATA2 deficiency | AD | GATA2 | TF network | MDS, AML, CMML |
| Disorders of abnormal hematopoiesis | ||||
| FPDMM | AD | RUNX1 | TF network | MDS, AML, T-ALL |
| THC2 | AD | ANKRD26 | MAPK signaling | MDS, AML, CML |
| THC5 | AD | ETV6 | TF network | MDS, B-ALL, MP-ALL |
| Isolated cancer/leukemia predisposition | ||||
| LFS | AD | TP53 | DNA damage/repair | AML, ALL, sAML |
| CMMRD | AR | MLH1, MSH2, MSH6, and PMS2 | DNA damage/repair | T-NHL, B-NHL, T-ALL, B-ALL, MDS, AML |
| CEBPA mutation | AD | CEBPA | TF network | AML |
| DDX41 mutation | AD | DDX41 | RNA splicing and/or telomere maintenance? | MDS, AML, CML, HL, NHL |
| PAX5 mutation | AD | PAX5 | TF network | B-ALL |
| Emerging leukemia predisposition syndromes | ||||
| ATG2B/GSKIP duplication | AD | ATG2/GSKIP | Unknown | MPN, AML |
| ACD mutation | AD | ACD | Telomere maintenance? | BMF |
| SRP72 mutation | AD | SRP72 | Unknown | MDS |
| SH2B3 mutation | AR | SH2B3 | JAK/STAT signaling | B-ALL |
| RBBP6 mutation | AD | RBBP6 | DNA damage/repair? | MPN |
| LAPTM5 and HCLS1 mutations | AD | LAPTM5 and HCLS1 | Unknown | WM |
| Predisposition . | Inheritance . | Genes . | Altered pathway/function . | Hematologic malignancies . |
|---|---|---|---|---|
| Syndromic predispositions to leukemia | ||||
| FA | AR, XLR | FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, FANCM, and FANCT; | DNA damage/repair | MDS, AML |
| FANCI and FANCD2; | ||||
| BRCA2/FANCD1, BRCA1/FANCS, FANCR/RAD51, FANCJ, FANCN, FANCO, FANCP, and FANCQ | ||||
| Dyskeratosis congenita | AD, AR, XLR | DKC1, TERC, and TINF2 | Telomere maintenance | MDS, AML |
| TERT, NHP2, NOP10, WRAP53, RTEL1, CTC1, PARN | ||||
| Down syndrome | Sporadic | Unknown | Multifactorial | AMKL, ALL |
| RASopathies | AD | NF1, PTPN11, KRAS, NRAS, SOS1, RAF1, CBL, SHOC2, HRAS, BRAF, MEK1, MEK2, and SPRED1 | RAS signaling | NS-MPD, JMML |
| GATA2 deficiency | AD | GATA2 | TF network | MDS, AML, CMML |
| Disorders of abnormal hematopoiesis | ||||
| FPDMM | AD | RUNX1 | TF network | MDS, AML, T-ALL |
| THC2 | AD | ANKRD26 | MAPK signaling | MDS, AML, CML |
| THC5 | AD | ETV6 | TF network | MDS, B-ALL, MP-ALL |
| Isolated cancer/leukemia predisposition | ||||
| LFS | AD | TP53 | DNA damage/repair | AML, ALL, sAML |
| CMMRD | AR | MLH1, MSH2, MSH6, and PMS2 | DNA damage/repair | T-NHL, B-NHL, T-ALL, B-ALL, MDS, AML |
| CEBPA mutation | AD | CEBPA | TF network | AML |
| DDX41 mutation | AD | DDX41 | RNA splicing and/or telomere maintenance? | MDS, AML, CML, HL, NHL |
| PAX5 mutation | AD | PAX5 | TF network | B-ALL |
| Emerging leukemia predisposition syndromes | ||||
| ATG2B/GSKIP duplication | AD | ATG2/GSKIP | Unknown | MPN, AML |
| ACD mutation | AD | ACD | Telomere maintenance? | BMF |
| SRP72 mutation | AD | SRP72 | Unknown | MDS |
| SH2B3 mutation | AR | SH2B3 | JAK/STAT signaling | B-ALL |
| RBBP6 mutation | AD | RBBP6 | DNA damage/repair? | MPN |
| LAPTM5 and HCLS1 mutations | AD | LAPTM5 and HCLS1 | Unknown | WM |
AD, autosomal dominant; ALL, acute lymphoblastic leukemia; AMKL, acute megakaryocytic leukemia; AML, acute myeloid leukemia; AR, autosomal recessive; B-ALL, B-cell acute lymphoblastic leukemia; B-NHL, B-cell NHL; CML, chronic myeloid leukemia; CMML, chronic myelomonocytic leukemia; CMMRD, constitutional mismatch repair deficiency; FPDMM, familial platelet disorder with associated myeloid malignancy; HL, Hodgkin lymphoma; JMML, juvenile myelomonocytic leukemia; MAPK, mitogen-activated protein kinase; MDS, myelodysplastic syndrome; MP-ALL, mixed phenotype acute lymphoblastic leukemia; MPN, myeloproliferative neoplasm; NF1, neurofibromatosis type 1; NHL, non-Hodgkin lymphoma; NS-MPD, Noonan syndrome-associated myeloproliferative disease; sAML, secondary AML; T-ALL, T-cell acute lymphoblastic leukemia; TF, transcription factor; THC, thrombocytopenia; T-NHL, T-cell NHL; WM, Waldenström macroglobulinemia; XLR, X-linked recessive.