Myeloid neoplasms with germline predisposition
| Syndrome name . | Gene . | Inheritance . | Age of onset . | Predisposition to other cancers . | Clinical features . |
|---|---|---|---|---|---|
| Myeloid neoplasms with germline predisposition without a preexisting platelet disorder or organ dysfunction | |||||
| Germline predisposition due to CEBPA P/LP variants* | CEBPA* | AD | Wide range | Not yet described | 2nd allele mutations are common, typically at the 3′ end Without allogeneic HCT, individuals are susceptible to additional malignancies |
| Germline predisposition due to DDX41 P/LP variants | DDX41 | AD | Adult > childhood | Likely | Male mutation carriers appear to develop myeloid malignancies more often than female mutation carriers Age of onset of myeloid malignancies similar to the general population R525H hotspot occurs commonly in myeloid malignancies as a somatic mutation |
| Li-Fraumeni syndrome | TP53 | AD | Wide age range | Yes | Predisposition to several tumor types |
| Myeloid neoplasms with germline predisposition and preexisting platelet disorders† | |||||
| Germline predisposition due to RUNX1 P/LP variants‡ | RUNX1‡ | AD | Wide age range | Myeloid malignancies > T-ALL > B-cell malignancies | Life-long thrombocytopenia and qualitative platelet defects |
| Germline predisposition due to ANKRD26 P/LP variants | ANKRD26 | AD | Adult > childhood | Not yet described | Life-long thrombocytopenia, various platelet function abnormalities No syndromic features |
| Germline predisposition due to ETV6 P/LP variants | ETV6 | AD | Wide age range | ALL > myeloid malignancies | Life-long thrombocytopenia |
| Myeloid neoplasms with germline predisposition and potential organ dysfunction | |||||
| Germline predisposition due to GATA2 P/LP variants | GATA2 | AD | Adolescents and young adults | Yes | Associated with immunodeficiencies, lymph edema, and many other phenotypes |
| Severe congenital neutropenia | ELANE, G6PC3GFI1, HAX1, JAGN, TCRG1, VPS45A | AD, AR | Adolescents and young adults | Not yet described | Severe opportunistic infections without growth factor support |
| Shwachman-Diamond syndrome | SBDS (> 90%), DNAJC21, EFL1, SRP54 | AR | Childhood > adult | Not yet described | Exocrine pancreas dysfunction, variable cytopenias, skeletal dysplasia, hepatomegaly and transaminitis in early childhood, may present as nonsyndromic AA or MDS/AML |
| Fanconi anemia | FANC A-W | AR | Childhood > adult | Yes | Congenital malformations, facial dysmorphism, BM failure, squamous cell carcinomas and liver tumors, sensitivity to genotoxic agents |
| Telomere biology disorders/short telomere syndromes | ACD, CTC1, DKC1, MDM4, RTEL1, TERC, TERT, TINF2, ACD, NHP2, NOP10, NPM1, PARN, WRAP53, RPA1, Apollo | AD, AR, and X-linked | Wide age range | Yes | Mucocutaneous triad of nail/hair abnormalities, skin rash, leukoplakia BM failure, pulmonary fibrosis, liver cirrhosis, vascular anomalies, squamous cell carcinoma May present as nonsyndromic AA or monosomy 7 MDS |
| CBL syndrome | CBL | AD | Early childhood | Not yet described | JMML/Noonan syndrome-like: facial dysmorphism, cardiac disease, musculoskeletal anomalies, cognitive deficits, vasculopathy; variable syndrome expressivity |
| Noonan syndrome | PTPN11, NRAS, KRAS | AD | Early childhood | ALL, AML, various non-hematologic cancers | Facial dysmorphism, cardiopathy, chylothorax, hygroma, and later in life short stature |
| Neurofibromatosis type I | NF1 | AD | Childhood > adult | Yes | Café au lait, neurofibromas Noonan syndrome-like disorder |
| Germline predisposition due to SAMD9 P/LP variants | SAMD9 | AD | Childhood > adult | Not yet described | MIRAGE syndrome: MDS with Infections, Renal abnormalities, Adrenal Insufficiency, Genitourinary anomalies, Enteropathy May present as non-syndromic monosomy 7 MDS or BM failure |
| Germline predisposition due to SAMD9L P/LP variants | SAMD9L | AD | Childhood > adult | Not yet described | Ataxia-pancytopenia syndrome May present as non-syndromic monosomy 7 MDS or BM failure |
| Bloom syndrome | BLM | AR | Childhood > adult | Yes | Prenatal growth deficiency, mild immunodeficiency, excessive photosensitivity with facial lupus-like skin lesions, type 2 diabetes mellitus, hypogonadism |
| Germline predisposition genes causing multiple cancer types including myeloid neoplasms | |||||
| Germline predisposition due to CHEK2 P/LP variants | CHEK2 | AD | Adult > childhood | Yes | Predisposition to clonal hematopoiesis and several tumor types |
| Germline predisposition due to MPL P/LP variants | MPL | AR, AD | Adult > childhood | Also associated with lymphoid malignancies | Thrombocytopenia: AR (homozygous and compound heterozygous); thrombocytosis: AD |
| Germline predisposition due to RECQL4 P/LP variants | RECQL4 | AR | Adult > childhood | Yes | Atrophic skin and pigment changes Alopecia, osteopenia, cataracts |
| Hereditary breast and ovarian cancer | BRCA1 | AD | Adult > childhood | Yes | Predisposition to several tumor types |
| Hereditary breast and ovarian cancer | BRCA2 | AD | Adult > childhood | Yes | Predisposition to several tumor types |
| Lynch syndrome | MLH1, MSH2, MSH6, PMS2 | AD, AR | Adult > childhood | Yes | Tumors show microsatellite instability |
| Nijmegen breakage syndrome | NBN | AR | Childhood > adult | Yes | >90% are homozygous for a 5-base pair deletion founder mutation Microcephaly at birth and progressive with age, dysmorphic facial features, mild growth retardation, intellectual disability, combined cellular and humoral immunodeficiency with recurrent sino-pulmonary infections, females with hypergonadotropic hypogonadism |
| Wiskott-Aldrich syndrome | WAS | X-linked | Adult > childhood | Yes | Immunodeficiency with microthrombocytopenia and neutropenia, eczema, recurrent infections, autoimmunity |
| Emerging disorders§ | |||||
| Germline predisposition due to CSF3R P/LP variants | CSF3R | AD | Adult > childhood | Not yet described | Full syndrome description awaits publication of additional cases |
| Germline predisposition due to ERCC6L2 P/LP variants | ERCC6L2 | AR (homozygous) | Adult > childhood | Not yet described | Full syndrome description awaits publication of additional cases |
| Germline predisposition due to JAK2 P/LP variants | JAK2 | AD | Adult > childhood | Not yet described | Associated with thrombocythemia |
| Germline predisposition due to MBD4 P/LP variants | MBD4 | AD | Adult > childhood | Likely | Myeloid malignancies have a high mutational rate Somatic mutation of DNMT3A is common |
| Germline predisposition due to MECOM/EVI1 P/LP variants | MECOM/EVI1 | AD | Childhood > adult | Not yet described | Radioulnar synostosis, clinodactyly, cardiac and renal malformations, presenile hearing loss BM failure, B-cell deficiency |
| Germline predisposition due to NPM1 P/LP variants | NPM1 | AD | Childhood > adult | Not yet described | Full syndrome description awaits publication of additional cases |
| Germline predisposition due to RBBP6 P/LP variants | RBBP6 | AD | Adult > childhood | Not yet described | Full syndrome description awaits publication of additional cases |
| Germline predisposition due to SRP72 P/LP variants | SRP72 | AD | Wide age range | Not yet described | Full syndrome description awaits publication of additional cases |
| Germline predisposition due to TET2 P/LP variants | TET2 | AD, AR | Childhood > adult | Not yet described | Full syndrome description awaits publication of additional cases |
| Syndrome name . | Gene . | Inheritance . | Age of onset . | Predisposition to other cancers . | Clinical features . |
|---|---|---|---|---|---|
| Myeloid neoplasms with germline predisposition without a preexisting platelet disorder or organ dysfunction | |||||
| Germline predisposition due to CEBPA P/LP variants* | CEBPA* | AD | Wide range | Not yet described | 2nd allele mutations are common, typically at the 3′ end Without allogeneic HCT, individuals are susceptible to additional malignancies |
| Germline predisposition due to DDX41 P/LP variants | DDX41 | AD | Adult > childhood | Likely | Male mutation carriers appear to develop myeloid malignancies more often than female mutation carriers Age of onset of myeloid malignancies similar to the general population R525H hotspot occurs commonly in myeloid malignancies as a somatic mutation |
| Li-Fraumeni syndrome | TP53 | AD | Wide age range | Yes | Predisposition to several tumor types |
| Myeloid neoplasms with germline predisposition and preexisting platelet disorders† | |||||
| Germline predisposition due to RUNX1 P/LP variants‡ | RUNX1‡ | AD | Wide age range | Myeloid malignancies > T-ALL > B-cell malignancies | Life-long thrombocytopenia and qualitative platelet defects |
| Germline predisposition due to ANKRD26 P/LP variants | ANKRD26 | AD | Adult > childhood | Not yet described | Life-long thrombocytopenia, various platelet function abnormalities No syndromic features |
| Germline predisposition due to ETV6 P/LP variants | ETV6 | AD | Wide age range | ALL > myeloid malignancies | Life-long thrombocytopenia |
| Myeloid neoplasms with germline predisposition and potential organ dysfunction | |||||
| Germline predisposition due to GATA2 P/LP variants | GATA2 | AD | Adolescents and young adults | Yes | Associated with immunodeficiencies, lymph edema, and many other phenotypes |
| Severe congenital neutropenia | ELANE, G6PC3GFI1, HAX1, JAGN, TCRG1, VPS45A | AD, AR | Adolescents and young adults | Not yet described | Severe opportunistic infections without growth factor support |
| Shwachman-Diamond syndrome | SBDS (> 90%), DNAJC21, EFL1, SRP54 | AR | Childhood > adult | Not yet described | Exocrine pancreas dysfunction, variable cytopenias, skeletal dysplasia, hepatomegaly and transaminitis in early childhood, may present as nonsyndromic AA or MDS/AML |
| Fanconi anemia | FANC A-W | AR | Childhood > adult | Yes | Congenital malformations, facial dysmorphism, BM failure, squamous cell carcinomas and liver tumors, sensitivity to genotoxic agents |
| Telomere biology disorders/short telomere syndromes | ACD, CTC1, DKC1, MDM4, RTEL1, TERC, TERT, TINF2, ACD, NHP2, NOP10, NPM1, PARN, WRAP53, RPA1, Apollo | AD, AR, and X-linked | Wide age range | Yes | Mucocutaneous triad of nail/hair abnormalities, skin rash, leukoplakia BM failure, pulmonary fibrosis, liver cirrhosis, vascular anomalies, squamous cell carcinoma May present as nonsyndromic AA or monosomy 7 MDS |
| CBL syndrome | CBL | AD | Early childhood | Not yet described | JMML/Noonan syndrome-like: facial dysmorphism, cardiac disease, musculoskeletal anomalies, cognitive deficits, vasculopathy; variable syndrome expressivity |
| Noonan syndrome | PTPN11, NRAS, KRAS | AD | Early childhood | ALL, AML, various non-hematologic cancers | Facial dysmorphism, cardiopathy, chylothorax, hygroma, and later in life short stature |
| Neurofibromatosis type I | NF1 | AD | Childhood > adult | Yes | Café au lait, neurofibromas Noonan syndrome-like disorder |
| Germline predisposition due to SAMD9 P/LP variants | SAMD9 | AD | Childhood > adult | Not yet described | MIRAGE syndrome: MDS with Infections, Renal abnormalities, Adrenal Insufficiency, Genitourinary anomalies, Enteropathy May present as non-syndromic monosomy 7 MDS or BM failure |
| Germline predisposition due to SAMD9L P/LP variants | SAMD9L | AD | Childhood > adult | Not yet described | Ataxia-pancytopenia syndrome May present as non-syndromic monosomy 7 MDS or BM failure |
| Bloom syndrome | BLM | AR | Childhood > adult | Yes | Prenatal growth deficiency, mild immunodeficiency, excessive photosensitivity with facial lupus-like skin lesions, type 2 diabetes mellitus, hypogonadism |
| Germline predisposition genes causing multiple cancer types including myeloid neoplasms | |||||
| Germline predisposition due to CHEK2 P/LP variants | CHEK2 | AD | Adult > childhood | Yes | Predisposition to clonal hematopoiesis and several tumor types |
| Germline predisposition due to MPL P/LP variants | MPL | AR, AD | Adult > childhood | Also associated with lymphoid malignancies | Thrombocytopenia: AR (homozygous and compound heterozygous); thrombocytosis: AD |
| Germline predisposition due to RECQL4 P/LP variants | RECQL4 | AR | Adult > childhood | Yes | Atrophic skin and pigment changes Alopecia, osteopenia, cataracts |
| Hereditary breast and ovarian cancer | BRCA1 | AD | Adult > childhood | Yes | Predisposition to several tumor types |
| Hereditary breast and ovarian cancer | BRCA2 | AD | Adult > childhood | Yes | Predisposition to several tumor types |
| Lynch syndrome | MLH1, MSH2, MSH6, PMS2 | AD, AR | Adult > childhood | Yes | Tumors show microsatellite instability |
| Nijmegen breakage syndrome | NBN | AR | Childhood > adult | Yes | >90% are homozygous for a 5-base pair deletion founder mutation Microcephaly at birth and progressive with age, dysmorphic facial features, mild growth retardation, intellectual disability, combined cellular and humoral immunodeficiency with recurrent sino-pulmonary infections, females with hypergonadotropic hypogonadism |
| Wiskott-Aldrich syndrome | WAS | X-linked | Adult > childhood | Yes | Immunodeficiency with microthrombocytopenia and neutropenia, eczema, recurrent infections, autoimmunity |
| Emerging disorders§ | |||||
| Germline predisposition due to CSF3R P/LP variants | CSF3R | AD | Adult > childhood | Not yet described | Full syndrome description awaits publication of additional cases |
| Germline predisposition due to ERCC6L2 P/LP variants | ERCC6L2 | AR (homozygous) | Adult > childhood | Not yet described | Full syndrome description awaits publication of additional cases |
| Germline predisposition due to JAK2 P/LP variants | JAK2 | AD | Adult > childhood | Not yet described | Associated with thrombocythemia |
| Germline predisposition due to MBD4 P/LP variants | MBD4 | AD | Adult > childhood | Likely | Myeloid malignancies have a high mutational rate Somatic mutation of DNMT3A is common |
| Germline predisposition due to MECOM/EVI1 P/LP variants | MECOM/EVI1 | AD | Childhood > adult | Not yet described | Radioulnar synostosis, clinodactyly, cardiac and renal malformations, presenile hearing loss BM failure, B-cell deficiency |
| Germline predisposition due to NPM1 P/LP variants | NPM1 | AD | Childhood > adult | Not yet described | Full syndrome description awaits publication of additional cases |
| Germline predisposition due to RBBP6 P/LP variants | RBBP6 | AD | Adult > childhood | Not yet described | Full syndrome description awaits publication of additional cases |
| Germline predisposition due to SRP72 P/LP variants | SRP72 | AD | Wide age range | Not yet described | Full syndrome description awaits publication of additional cases |
| Germline predisposition due to TET2 P/LP variants | TET2 | AD, AR | Childhood > adult | Not yet described | Full syndrome description awaits publication of additional cases |
AA, aplastic anemia; AD, autosomal dominant; ALL, acute lymphoblastic leukemia; AR, autosomal recessive; JMML, juvenile myelomonocytic leukemia; LP, likely pathogenic; P, pathogenic.
Approximately 10% of patients with bi-allelic CEBPA-mutant AML have one of those alleles as a germline allele, typically the 5′-end mutation, although rare 3′-end germline mutations have been described. Germline 5′-end CEBPA mutations have a penetrance of close to 100%, in contrast to germline 3′-end mutations, which have lower penetrance. Because of the high penetrance of leukemia development in those with 5′ end germline mutations, some advocate pre-emptive allogeneic HCT. Leukemia survival appears to be longer for those with a germline mutation compared with those with two acquired mutations. The presence of the acquired CEBPA mutation serves as a molecular marker of AML, and these 3′-end acquired mutations are distinct in AML that re-emerge in germline CEBPA-mutation carriers, suggesting that they are independent primary AMLs rather than relapses. Therefore, individuals with germline CEBPA mutations who develop AML and are treated only with chemotherapy are at risk for developing independent AML, since their germline mutation remains. For this reason, some argue for allogeneic HCT in first remission for these patients.
Among these, all show phenotypic variability even within the same family. People with germline ANKRD26 mutations generally have the lowest platelet counts. Germline RUNX1 mutations cause myeloid malignancies > T-cell ALL > B-cell malignancies; germline ETV6 mutations cause B-cell ALL > myeloid malignancies; and germline ANKRD26 mutations have been associated only with myeloid malignancies to date.
Thirty percent of germline RUNX1-mutated patients have clonal hematopoiesis prior to leukemia development, where BCOR mutations predominate. When leukemias develop, somatic mutations in the wild-type RUNX1 allele are seen commonly along with acquired mutations in ASXL1, FLT3, GATA2, PHF6, SRSF2, and WT1.
Emerging disorders are so-named due to limited numbers of cases from the published literature at this time.