Myeloid Neoplasms with Germline Predisposition

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Primary Author(s)*

Jialing Huang, MD, PhD; Ying Zou, MD, PHD, FACMG

Johns Hopkins University, Baltimore, MD

General Disease Overview / Description of Cancer Category

Increasingly performed high throughput molecular assays enable deeper and comprehensive understanding of genetic changes in neoplasms, which reflect tumor biology and behavior. Simultaneously, many underlying germline mutations of genes accounting for solid and hematopoietic neoplasms have been progressively identified. These patients usually have an early onset of myeloid malignancies (younger patients), evidence of disease anticipation, multiple cases of myeloid malignancies with multiple generations in a pedigree, and/or life-long defects in platelet number and dysfunction, and/or a personal history of multiple cancers. It is known that familial myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are driven by genomic alterations such as mutations in genes encoding transcription factors (GATA-2, RUNX1, ETV6, and CEBPα) involved in hematopoietic stem and progenitor cell (HSPC) development and differentiation. On this basis, a group of hereditary myeloid disorder (HMD) have been incorporated in the WHO 2016 classification of myeloid neoplasms and acute leukemia [1].

There are three categories of genetic predisposed myeloid malignancies:

(1) Familial myelodysplastic syndrome and acute myeloid leukemia caused by germline mutations in ANKRD26, CEBPA, DDX41, ETV6, GATA2, RUNX1, MSH6, DDX41, SAMD9, SAMD9L and SRP72 genes. About 5% to 10% of patients with MDS and/or AML carry germline mutations in these genes.

(2) Familial cancer syndromes associated with increased risk of multiple types of malignancies in addition to myelodysplasia (MDS) and acute myeloid leukemia (AML), such as Li-Fraumeni syndrome (TP53 gene), Bloom syndrome (BLM gene),  and constitutional mismatch repair deficiency (CMMRD; also known as biallelic mismatch repair deficiency (BMMRD)), neurofibromatosis type I, Nijmegen breakage syndrome (NBS) and Noonan syndrome.

(3) Familial pediatric inherited bone marrow failure syndromes, including Fanconi anemia (FA), dyskeratosis congenital (DC), severe congenital neutropenia (SCN), Shwachman-Diamond syndrome (SDS), MIRAGE syndrome and Diamond Blackfan anemia (DBA). These syndromes are caused by mutations in more than one gene, except for SDS and MIRAGE syndrome, which are caused by SDBS and SMAD9 gene mutation, respectively.

The patients with pathogenic mutations of these susceptibility genes usually have characteristic clinical features and should be managed differently from those sporadic cases with a multidisciplinary team. Detailed family and medical history and appropriate genetic testing and counseling are important for recognition and detection of these conditions, and close monitoring is vital for early identification of malignant transformation.  

WHO Classification Pages (Includes Links to Content)

Other Related Pages (Includes Links to Content)


Additional Information

  • ANKRD26 (OMIM: 610855) has been associated with thrombocytopenia 2 (OMIM: 188000)
  • CEBPA (OMIM: 116897) has been associated with acute myeloid leukemia (OMIM: 601626)
  • DDX41 (OMIM: 608170) has been associated with susceptibility to multiple types of familial myeloproliferative/lymphoproliferative neoplasms (OMIM: 616871)
  • ETV6 (OMIM: 600618) has been associated with thrombocytopenia 5 (OMIM: 616216)
  • GATA2 (OMIM: 137295) has been associated with susceptibility to acute myeloid leukemia (OMIM: 601626)
  • RUNX1 (OMIM: 151385) has been associated with acute myeloid leukemia (OMIM: 601626) and familial platelet disorder with associated myeloid malignancy (OMIM: 601399)
  • SAMD9 (OMIM: 610456) has been associated with Myelodysplasia, Infection, Restriction of growth, Adrenal hypoplasia, Genital phenotypes, and Enteropathy (MIRAGE syndrome, (OMIM: 617053)
  • SAMD9L (OMIM: 611170) has been associated with ataxia-pancytopenia syndrome, or myelocerebellar disorder, ataxia-pancytopenia syndrome (OMIM: 159550)
  • SRP72 (OMIM: 602122) has been associated with bone marrow failure syndrome 1 (OMIM: 614675)
  • TP53 (OMIM: 191170) has been associated with Li-Fraumeni syndrome (OMIM: 151623)
  • BLM (OMIM: 604610) has been associated with Bloom syndrome (OMIM: 210900)
  • Constitutional mismatch repair deficiency (OMIM: 276300)
  • Neurofibromatosis type I (NF1, OMIM: 162200)
  • Nijmegen breakage syndrome (NBS, OMIM: 251260)
  • Noonan syndrome (please see Genetic heterogeneity of Noonan syndrome at OMIM: 163950)
  • Fanconi anemia (FA, please see Genetic heterogeneity of Fanconi anemia at OMIM: 227650)
  • Dyskeratosis congenital (DC, please see Genetic heterogeneity of dyskeratosis congenital at OMIM: 127550)
  • Severe congenital neutropenia (SCN, please see Genetic heterogeneity of severe congenital neutropenia at OMIM; 202700)
  • Shwachman-Diamond syndrome 1 (SDS1, OMIM: 260400) and Shwachman-Diamond syndrome 2 (SDS2, OMIM: 617941)
  • Diamond Blackfan anemia (DBA, please see Genetic heterogeneity of Diamond Blackfan anemia at OMIM: 105650)


  1. Peterson LC, et al., (2017). Myeloid neoplasms with germline predisposition, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p122-128.


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*Citation of this Page: Huang J, Zou Y. “Myeloid Neoplasms with Germline Predisposition”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 03/3/2021,

*The hierarchical tumour classification structure displayed on this page is reproduced from the WHO Classification of Tumours with permission from the copyright holder, ©International Agency for Research on Cancer.