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Blood Res (2024) 59:12
Published online March 8, 2024
https://doi.org/10.1007/s44313-024-00012-y
© The Korean Society of Hematology
Genomic testing for germline predisposition to hematologic malignancies
Sang Mee Hwang1* 
Correspondence to : *Sang Mee Hwang
sangmee1@snu.ac.kr
Germline predisposition (GPD) to hematological malignancies has gained interest because of the increased use of genetic testing in this field. Recent studies have suggested that GPD is underrecognized and requires appropriate genomic testing for an accurate diagnosis. Identification of GPD significantly affects patient management and has diverse implications for family members. This review discusses the reasons for testing GPD in hematologic malignancies and explores the considerations necessary for appropriate genomic testing. The aim is to provide insights into how these genetic insights can inform treatment strategies and genetic counseling, ultimately enhancing patient care.
Keywords Germline predisposition, Hematologic malignancies, Genomic testing, Myeloid neoplasms, Next-generation sequencing
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REVIEW
Blood Res 2024; 59():
Published online March 8, 2024 https://doi.org/10.1007/s44313-024-00012-y
Copyright © The Korean Society of Hematology.
Genomic testing for germline predisposition to hematologic malignancies
Sang Mee Hwang1*
1Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Gumiro 173 Beongil‑82, Bundanggu, Seongnam, Gyeonggido 13620, South Korea
Correspondence to:*Sang Mee Hwang
sangmee1@snu.ac.kr
Abstract
Germline predisposition (GPD) to hematological malignancies has gained interest because of the increased use of genetic testing in this field. Recent studies have suggested that GPD is underrecognized and requires appropriate genomic testing for an accurate diagnosis. Identification of GPD significantly affects patient management and has diverse implications for family members. This review discusses the reasons for testing GPD in hematologic malignancies and explores the considerations necessary for appropriate genomic testing. The aim is to provide insights into how these genetic insights can inform treatment strategies and genetic counseling, ultimately enhancing patient care.
Keywords: Germline predisposition, Hematologic malignancies, Genomic testing, Myeloid neoplasms, Next-generation sequencing
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Table 1 . WHO 5th Edition and ICC for myeloid/hematologic neoplasms with GPD.
WHO 5th Edition ICC Myeloid neoplasms with GPD without a pre-existing platelet disorder or organ dysfunction.
Germline CEBPA P/LP variant (CEBPA-associated familial AML) Germline DDX41 P/LP varianta.
Germline TP53 P/LP variant (Li Fraumeni syndrome)a.
Myeloid neoplasms with GPD and pre-existing platelet disorder.
Germline RUNX1 P/LP varianta (Familial platelet disorder with associated myeloid malignancy, FPD-MM).
Germline ANKRD26 P/LP varianta (Thrombocytopenia 2).
Germline ETV6 P/LP varianta (Thrombocytopenia 5).
Myeloid neoplasms with GPD and potential organ dysfunction.
Germline GATA2 P/LP variant (GATA2 deficiency).
Germline SAMD9 P/LP variant (MIRAGE syndrome).
Germline SAMD9L P/LP variant (SAMD9L-related ataxia pancytopenia Syndrome).
RASopathies (Neurofibromatosis type 1, CBL syndrome, Noonan syndrome or Noonan-syndrome-like disordersa).
Down syndromea.
Bi-allelic germline BLM P/LP variant (Bloom syndrome).
Bone marrow failure syndromes:.
- FA.
- SDS.
- DBA.
- Severe congenital neutropenia.
- Telomere biology disorders.
Hematologic neoplasms with GPD without a constitutional disorder affecting multiple organ systems.
Myeloid neoplasms with germline CEBPA mutation.
Myeloid or lymphoid neoplasms with germline DDX41 mutation.
Myeloid or lymphoid neoplasms with germline TP53 mutation Hematologic neoplasms with GPD associated with a constitutional platelet disorder.
Myeloid or lymphoid neoplasms with germline RUNX1 mutation.
Myeloid neoplasms with germline ANKRD26 mutation.
Myeloid or lymphoid neoplasms with germline ETV6 mutation Hematologic neoplasms with GPD associated with a constitutional disorder affecting multiple organ systems.
Myeloid neoplasm with germline GATA2 mutation Myeloid neoplasm with germline SAMD9 mutation Myeloid neoplasm with germline SAMD9L mutation.
Juvenile myelomonocytic leukemia associated with neurofibromatosis.
Juvenile myelomonocytic leukemia associated with Noonan-syndrome-like disorder (CBL syndrome).
Myeloid or lymphoid neoplasms associated with Down syndrome.
Myeloid neoplasms associated with bone marrow failure syndromes:.
- FA.
- SDS.
- DBA.
- Severe congenital neutropenia.
- Telomere biology disorders including dyskeratosis congenita Acute lymphoblastic leukemia with GPDb.
Acute lymphoblastic leukemia with germline PAX5 mutation Acute lymphoblastic leukemia with germline IKZF1 mutation.
Abbreviations: P Pathogenic, LP Likely pathogenic.
a Lymphoid neoplasms can also occur.
b Down syndrome and germline mutations in ETV6 or TP53 also predispose to acute lymphoblastic leukemia.
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