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Hereditary Predisposition to Hematopoietic Neoplasms

When Bloodline Matters for Blood Cancers

      Abstract

      With the advent of precision genomics, hereditary predisposition to hematopoietic neoplasms— collectively known as hereditary predisposition syndromes (HPS)—are being increasingly recognized in clinical practice. Familial clustering was first observed in patients with leukemia, which led to the identification of several germline variants, such as RUNX1, CEBPA, GATA2, ANKRD26, DDX41, and ETV6, among others, now established as HPS, with tendency to develop myeloid neoplasms. However, evidence for hereditary predisposition is also apparent in lymphoid and plasma--cell neoplasms, with recent discoveries of germline variants in genes such as IKZF1, SH2B3, PAX5 (familial acute lymphoblastic leukemia), and KDM1A/LSD1 (familial multiple myeloma). Specific inherited bone marrow failure syndromes—such as GATA2 haploinsufficiency syndromes, short telomere syndromes, Shwachman-Diamond syndrome, Diamond-Blackfan anemia, severe congenital neutropenia, and familial thrombocytopenias—also have an increased predisposition to develop myeloid neoplasms, whereas inherited immune deficiency syndromes, such as ataxia-telangiectasia, Bloom syndrome, Wiskott Aldrich syndrome, and Bruton agammaglobulinemia, are associated with an increased risk for lymphoid neoplasms. Timely recognition of HPS is critical to ensure safe choice of donors and/or conditioning-regimen intensity for allogeneic hematopoietic stem-cell transplantation and to enable direction of appropriate genomics-driven personalized therapies. The purpose of this review is to provide a comprehensive overview of HPS and serve as a useful reference for clinicians to recognize relevant signs and symptoms among patients to enable timely screening and referrals to pursue germline assessment. In addition, we also discuss our institutional approach toward identification of HPS and offer a stepwise diagnostic and management algorithm.

      Abbreviations and Acronyms:

      AA (aplastic anemia), ALL (acute lymphoblastic leukemia), AML (acute myeloid leukemia), CAMT (congenital amegakaryocytic thrombocytopenia), CLL (chronic lymphocytic leukemia), CMML (chronic myelomonocytic leukemia), DBA (Diamond-Blackfan anemia), G-CSF (granulocyte-colony stimulating factor), HCT (hematopoietic stem cell transplantation), HL (Hodgkin lymphoma), HPS (hereditary predisposition syndrome), IBFMS (inherited bone marrow failure syndrome), MDS (myelodysplastic syndrome), MM (multiple myeloma), MPN (myeloproliferative neoplasm), NHL (non-Hodgkin lymphoma), SCN (severe congenital neutropenia), STS (short telomere syndrome), TAR (thrombocytopenia absent radii), WHO (World Health Organization)
      Article Highlights
      • Among hematopoietic neoplasms, hereditary predisposition is being increasingly recognized in clinical practice.
      • It is important for clinicians to recognize the subtle clinical signs and symptoms to diagnose and manage patients expeditiously.
      • Identifying a hereditary predisposition can have significant therapeutic implications for patients with hematopoietic neoplasms.
      As genetic sequencing approaches are increasingly being integrated in clinical oncology and hematology, a number of germline genetic variants are being discovered in patients with cancer and their family members, also known as hereditary predisposition syndromes (HPS). For hematopoietic malignancies, familial clustering was first identified in several families with chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML).
      • Gunz F.
      • Dameshek W.
      Chronic lymphocytic leukemia in a family, including twin brothers and a son.
      • Fitzgerald P.H.
      • Crossen P.E.
      • Adams A.C.
      • Sharman C.V.
      • Gunz F.W.
      Chromosome studies in familial leukaemia.
      • Gunz F.W.
      • Gunz J.P.
      • Veale A.M.
      • Chapman C.J.
      • Houston I.B.
      Familial leukaemia: a study of 909 families.
      • Gunz F.W.
      • Gunz J.P.
      • Vincent P.C.
      • et al.
      Thirteen cases of leukemia in a family.
      Since then, several putative germline variants have been associated with myeloid neoplasms such as RUNX1
      • Song W.J.
      • Sullivan M.G.
      • Legare R.D.
      • et al.
      Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia.
      (for expansion of gene symbols, go to www.genenames.org), CEBPA,
      • Smith M.L.
      • Cavenagh J.D.
      • Lister T.A.
      • Fitzgibbon J.
      Mutation of CEBPA in familial acute myeloid leukemia.
      GATA2,
      • Ostergaard P.
      • Simpson M.A.
      • Connell F.C.
      • et al.
      Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome).
      ANKRD26,
      • Noris P.
      • Perrotta S.
      • Seri M.
      • et al.
      Mutations in ANKRD26 are responsible for a frequent form of inherited thrombocytopenia: analysis of 78 patients from 21 families.
      ,
      • Pippucci T.
      • Savoia A.
      • Perrotta S.
      • et al.
      Mutations in the 5' UTR of ANKRD26, the ankirin repeat domain 26 gene, cause an autosomal-dominant form of inherited thrombocytopenia, THC2.
      DDX41,
      • Polprasert C.
      • Schulze I.
      • Sekeres M.A.
      • et al.
      Inherited and somatic defects in DDX41 in myeloid neoplasms.
      ETV6,
      • Zhang M.Y.
      • Churpek J.E.
      • Keel S.B.
      • et al.
      Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy.
      TERC/TERT,
      • Townsley D.M.
      • Dumitriu B.
      • Young N.S.
      Bone marrow failure and the telomeropathies.
      and SRP72,
      • Kirwan M.
      • Beswick R.
      • Walne A.J.
      • et al.
      Dyskeratosis congenita and the DNA damage response.
      along with those (such as TP53
      • Levine A.J.
      • Momand J.
      • Finlay C.A.
      The p53 tumour suppressor gene.
      ) implicated in established cancer predisposition syndromes. In recognition of these discoveries, the latest iteration of the World Health Organization (WHO) classification of hematopoietic neoplasms now includes a separate category for myeloid neoplasms with a germline predisposition.
      • Arber D.A.
      • Orazi A.
      • Hasserjian R.
      • et al.
      The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.
      However, hereditary predisposition toward hematopoietic neoplasia is not only limited to those with a myeloid lineage cell of origin but also includes lymphoid and plasma-cell cancers, with recent discoveries of pathogenic variants in genes KDM1A/LSD1
      • Wei X.
      • Calvo-Vidal M.N.
      • Chen S.
      • et al.
      Germline lysine-specific demethylase 1 (LSD1/KDM1A) mutations confer susceptibility to multiple myeloma.
      and DIS3,
      • Pertesi M.
      • Vallee M.
      • Wei X.
      • et al.
      Exome sequencing identifies germline variants in DIS3 in familial multiple myeloma.
      among others. In light of these new findings, clinicians should have a high index of clinical suspicion in recognizing these entities, especially in patients with whom a typical family history or classical disease-associated signs and symptoms may be noticeably absent. Recognizing a germline predisposition has important clinical implications for both the patients (donor and/or conditioning regimen selection for allogeneic hematopoietic stem cell transplantation [HCT] and directing appropriate therapies) and their family members (screening and genetic counseling).
      In this review, we discuss hematopoietic neoplasms with a hereditary predisposition and provide an overview of a personalized management approach followed at the Mayo Clinic Center for Individualized Medicine Precision Medicine Clinic (IRB# 16-004173 and NCT#02958462), where patients with high indices of clinical suspicion for hereditary predisposition syndrome (HPS) undergo a stepwise approach, starting with counseling, targeted sequencing (targeted exome) (Supplemental Table 1 [available online at http://www,mayoclinicproceedings.org]) and, if negative, whole exome sequencing to identify candidate gene variants followed by confirmation on germline tissue or sequencing affected/unaffected family members.

      Myeloid Neoplasms

      Among hereditary hematopoietic neoplasms, hereditary myeloid malignancy syndromes (HMMS) are the best characterized, both clinically and genomically.
      • Patnaik M.M.
      • Lasho T.L.
      • Vijayvargiya P.
      • et al.
      Prognostic interaction between ASXL1 and TET2 mutations in chronic myelomonocytic leukemia.
      Despite considerable overlap—based on the presence or absence of characteristic syndromic features—these disorders can grouped as follows:

      Familial Thrombocytopenia With Predisposition to Myeloid Malignancies

      Initial linkage analysis studies among families with AML and familial platelet disorders revealed clustering at chromosome 21q22.1-22.2 loci,
      • Ho C.Y.
      • Otterud B.
      • Legare R.D.
      • et al.
      Linkage of a familial platelet disorder with a propensity to develop myeloid malignancies to human chromosome 21q22.1-22.2.
      which led to the identification of germline RUNX1 haploinsufficiency (also called RUNX1-familial predisposition syndrome).
      • Song W.J.
      • Sullivan M.G.
      • Legare R.D.
      • et al.
      Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia.
      Other disorders include autosomal dominant variants in the 5’ untranslated region of ANKRD26 gene, which is associated with increased risk of myelodysplastic syndrome (MDS)/AML
      • Noris P.
      • Perrotta S.
      • Seri M.
      • et al.
      Mutations in ANKRD26 are responsible for a frequent form of inherited thrombocytopenia: analysis of 78 patients from 21 families.
      ,
      • Pippucci T.
      • Savoia A.
      • Perrotta S.
      • et al.
      Mutations in the 5' UTR of ANKRD26, the ankirin repeat domain 26 gene, cause an autosomal-dominant form of inherited thrombocytopenia, THC2.
      and germline missense pathogenic variants in the ETV6 gene, which increases predisposition to a heterogeneous group of hematologic malignancies (multiple myeloma [MM], pre–B-cell acute lymphoblastic leukemia (ALL), MDS, chronic myelomonocytic leukemia (CMML), and biphenotypic acute leukemia).
      • Noris P.
      • Perrotta S.
      • Seri M.
      • et al.
      Mutations in ANKRD26 are responsible for a frequent form of inherited thrombocytopenia: analysis of 78 patients from 21 families.
      ,
      • Pippucci T.
      • Savoia A.
      • Perrotta S.
      • et al.
      Mutations in the 5' UTR of ANKRD26, the ankirin repeat domain 26 gene, cause an autosomal-dominant form of inherited thrombocytopenia, THC2.
      ,
      • Zhang M.Y.
      • Churpek J.E.
      • Keel S.B.
      • et al.
      Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy.
      ,
      • Albers C.A.
      • Paul D.S.
      • Schulze H.
      • et al.
      Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome.
      Additional details are mentioned in Table 1.
      • Albers C.A.
      • Paul D.S.
      • Schulze H.
      • et al.
      Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome.
      ,
      • Tonelli R.
      • Scardovi A.L.
      • Pession A.
      • et al.
      Compound heterozygosity for two different amino-acid substitution mutations in the thrombopoietin receptor (c-mpl gene) in congenital amegakaryocytic thrombocytopenia (CAMT).
      Table 1Hematological Disorders and Neoplasms With a Germline Predisposition and Associated Gene Mutations and/or Chromosomal Abnormalities
      Owing to the large number of genes, only a select few have been incorporated in the table.
      Genes involvedChromosomal locationGene functionAssociated neoplasms and hematologic disordersRef.
      Myeloid neoplasms and bone marrow-failure syndromes
      CEBPA19q13.11Enhancer/transcription factorAML
      • Smith M.L.
      • Cavenagh J.D.
      • Lister T.A.
      • Fitzgibbon J.
      Mutation of CEBPA in familial acute myeloid leukemia.
      DDX415q35.3RNA helicase functionMDS
      • Polprasert C.
      • Schulze I.
      • Sekeres M.A.
      • et al.
      Inherited and somatic defects in DDX41 in myeloid neoplasms.
      SRP724q12Endoplasmic reticulum functionMPN
      • Sarasin A.
      • Quentin S.
      • Droin N.
      • et al.
      Familial predisposition to TP53/complex karyotype MDS and leukemia in DNA repair-deficient xeroderma pigmentosum.
      MBD43q21.3Binding and protection of methylated DNA
      • Nagamachi A.
      • Matsui H.
      • Asou H.
      • et al.
      Haploinsufficiency of SAMD9L, an endosome fusion facilitator, causes myeloid malignancies in mice mimicking human diseases with monosomy 7.
      SAMD9/9L7q21.2DNA repair
      • Narumi S.
      • Amano N.
      • Ishii T.
      • et al.
      SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7.
      • Schwartz J.R.
      • Wang S.
      • Ma J.
      • et al.
      Germline SAMD9 mutation in siblings with monosomy 7 and myelodysplastic syndrome.
      • Maciaszek J.L.
      • Oak N.
      • Chen W.
      • et al.
      Enrichment of heterozygous germline RECQL4 loss-of-function variants in pediatric osteosarcoma.
      RECQL48q24.3DNA helicase (unwinding of DNA)
      • Stieglitz E.
      • Loh M.L.
      Genetic predispositions to childhood leukemia.
      • Ghosh A.K.
      • Rossi M.L.
      • Singh D.K.
      • et al.
      RECQL4, the protein mutated in Rothmund-Thomson syndrome, functions in telomere maintenance.
      • Tartaglia M.
      • Martinelli S.
      • Cazzaniga G.
      • et al.
      Genetic evidence for lineage-related and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia.
      PTPN1112q24.13Regulation of RAS/MAPK signaling pathwayCMML, JMML, Noonan syndrome
      • Martinelli S.
      • Stellacci E.
      • Pannone L.
      • et al.
      Molecular diversity and associated Phenotypic spectrum of germline CBL mutations.
      CBL11q23.3RAS pathway regulationJMML
      • Muraoka M.
      • Okuma C.
      • Kanamitsu K.
      • et al.
      Adults with germline CBL mutation complicated with juvenile myelomonocytic leukemia at infancy.
      ,
      • Kirwan M.
      • Walne A.J.
      • Plagnol V.
      • et al.
      Exome sequencing identifies autosomal-dominant SRP72 mutations associated with familial aplasia and myelodysplasia.
      RUNX121q22.12Transcription factorFamilial thrombocytopenia
      • Song W.J.
      • Sullivan M.G.
      • Legare R.D.
      • et al.
      Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia.
      ETV612p13.2Transcription factor
      • Zhang M.Y.
      • Churpek J.E.
      • Keel S.B.
      • et al.
      Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy.
      ANKRD2610p12.1Protein-protein interactions
      • Noris P.
      • Perrotta S.
      • Seri M.
      • et al.
      Mutations in ANKRD26 are responsible for a frequent form of inherited thrombocytopenia: analysis of 78 patients from 21 families.
      ,
      • Pippucci T.
      • Savoia A.
      • Perrotta S.
      • et al.
      Mutations in the 5' UTR of ANKRD26, the ankirin repeat domain 26 gene, cause an autosomal-dominant form of inherited thrombocytopenia, THC2.
      MECOM3q26.2Transcriptional regulator
      • Sanders M.A.
      • Chew E.
      • Flensburg C.
      • et al.
      MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML.
      RBM8A (5’UTR, 1st intron)1q21.1Cellular protein production
      • Albers C.A.
      • Paul D.S.
      • Schulze H.
      • et al.
      Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome.
      C-MPL1p34.2Cell proliferation
      • Tonelli R.
      • Scardovi A.L.
      • Pession A.
      • et al.
      Compound heterozygosity for two different amino-acid substitution mutations in the thrombopoietin receptor (c-mpl gene) in congenital amegakaryocytic thrombocytopenia (CAMT).
      ,
      • Tapper W.
      • Jones A.V.
      • Kralovics R.
      • et al.
      Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms.
      ELANE19p13.3Neutrophil elastase productionSevere congenital neutropenia
      • Ballmaier M.
      • Germeshausen M.
      • Schulze H.
      • et al.
      c-mpl mutations are the cause of congenital amegakaryocytic thrombocytopenia.
      HAX11q21.3Regulation of apoptosis
      • Boxer L.A.
      • Stein S.
      • Buckley D.
      • Bolyard A.A.
      • Dale D.C.
      Strong evidence for autosomal dominant inheritance of severe congenital neutropenia associated with ELA2 mutations.
      WASXp11.23Maintaining cellular structural framework
      • Matsubara K.
      • Imai K.
      • Okada S.
      • et al.
      Severe developmental delay and epilepsy in a Japanese patient with severe congenital neutropenia due to HAX1 deficiency.
      CSF3R1p34.3Granulocyte maturation and function
      • Touw I.P.
      Game of clones: the genomic evolution of severe congenital neutropenia.
      GATA23q21.3Zinc-finger transcription factorGATA2 haploinsufficiency syndrome
      • Ostergaard P.
      • Simpson M.A.
      • Connell F.C.
      • et al.
      Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome).
      TERT5p15.33Catalytic subunit of telomeraseShort telomere syndromes
      • Townsley D.M.
      • Dumitriu B.
      • Young N.S.
      Bone marrow failure and the telomeropathies.
      ,
      • Sanders M.A.
      • Chew E.
      • Flensburg C.
      • et al.
      MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML.
      ,
      • Beel K.
      • Vandenberghe P.
      G-CSF receptor (CSF3R) mutations in X-linked neutropenia evolving to acute myeloid leukemia or myelodysplasia.
      • Oddsson A.
      • Kristinsson S.Y.
      • Helgason H.
      • et al.
      The germline sequence variant rs2736100_C in TERT associates with myeloproliferative neoplasms.
      • Mangaonkar A.A.
      • Ferrer A.
      • Pinto E.V.F.
      • et al.
      Clinical correlates and treatment outcomes for patients with short telomere syndromes.
      TERC3q26.2Telomerase RNA component
      RTEL120q13.33DNA helicase (telomere protection)
      POT17q31.22Telomere maintenance
      FANCA16q24.3
      • Mangaonkar A.A.
      • Patnaik M.M.
      Short telomere syndromes in clinical practice: bridging bench and bedside.
      FANCBXp22.31
      FANCC9q22.3
      FANCD1/BRCA213q12.3
      FANCE6p21.3DNA repairFanconi anemia
      FANCF11p15
      FANCG9p13
      FANCI15q25-26
      FANCJ17q22.3
      FANCL2p16.1
      FANCM14q21.3
      FANCN16p12.1
      SBDS7q11.21RNA processingShwachman-Diamond syndrome
      • Shimamura A.
      • Alter B.P.
      Pathophysiology and management of inherited bone marrow failure syndromes.
      DNAJC215p13.2Co-chaperone for HSP70, RNA biogenesis
      • Boocock G.R.
      • Morrison J.A.
      • Popovic M.
      • et al.
      Mutations in SBDS are associated with Shwachman-Diamond syndrome.
      ,
      • Dhanraj S.
      • Matveev A.
      • Li H.
      • et al.
      Biallelic mutations in DNAJC21 cause Shwachman-Diamond syndrome.
      EFL115q25.2
      • D'Amours G.
      • Lopes F.
      • Gauthier J.
      • et al.
      Refining the phenotype associated with biallelic DNAJC21 mutations.
      RPS1919q13.2
      • Mangaonkar A.A.
      • Patnaik M.M.
      Short telomere syndromes in clinical practice: bridging bench and bedside.
      ,
      • Stepensky P.
      • Chacon-Flores M.
      • Kim K.H.
      • et al.
      Mutations in EFL1, an SBDS partner, are associated with infantile pancytopenia, exocrine pancreatic insufficiency and skeletal anomalies in aShwachman-Diamond like syndrome.
      ,
      • Lipton J.M.
      • Ellis S.R.
      Diamond-Blackfan anemia: diagnosis, treatment, and molecular pathogenesis.
      RPS2410q22.3
      RPS1715q25.2Ribosome assembly and function (all RPS and RPL genes)Diamond-Blackfan anemia
      RPL51p22.1
      RPL111p36.11
      RPL35A3q29
      GATA1Xp11.23Erythroid transcription factor
      • Lipton J.M.
      • Ellis S.R.
      Diamond-Blackfan anemia: diagnosis, treatment, and molecular pathogenesis.
      • Ulirsch J.C.
      • Verboon J.M.
      • Kazerounian S.
      • et al.
      The genetic landscape of Diamond-Blackfan anemia.
      • Vlachos A.
      • Rosenberg P.S.
      • Atsidaftos E.
      • Alter B.P.
      • Lipton J.M.
      Incidence of neoplasia in Diamond-Blackfan anemia: a report from the Diamond-Blackfan Anemia Registry.
      • Sankaran V.G.
      • Ghazvinian R.
      • Do R.
      • et al.
      Exome sequencing identifies GATA1 mutations resulting in Diamond-Blackfan anemia.
      • Ludwig L.S.
      • Gazda H.T.
      • Eng J.C.
      • et al.
      Altered translation of GATA1 in Diamond-Blackfan anemia.
      TSR2Xp11.22Ribosomal maturation factor
      • Klar J.
      • Khalfallah A.
      • Arzoo P.S.
      • Gazda H.T.
      • Dahl N.
      Recurrent GATA1 mutations in Diamond-Blackfan anaemia.
      ATG2B/GSKIP14q32.2Cell differentiationFamilial MPN
      • Gripp K.W.
      • Curry C.
      • Olney A.H.
      • et al.
      Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28.
      ,
      • Saliba J.
      • Saint-Martin C.
      • Di Stefano A.
      • et al.
      Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies.
       Trisomy 21--Down’s syndrome (with associated AML, ALL, TMD)
      • Babushok D.V.
      • Stanley N.L.
      • Morrissette J.J.D.
      • et al.
      Germline duplication of ATG2B and GSKIP genes is not required for the familial myeloid malignancy syndrome associated with the duplication of chromosome 14q32.
      Lymphoid neoplasms and immune deficiency syndromes
      IKZF17p12.2Transcription factorALL
      • Labuhn M.
      • Perkins K.
      • Matzk S.
      • et al.
      Mechanisms of progression of myeloid preleukemia to transformed myeloid leukemia in children with Down syndrome.
      PAX59p13.2Transcription factorNHL
      • Churchman M.L.
      • Qian M.
      • Te Kronnie G.
      • et al.
      Germline genetic IKZF1 variation and predisposition to childhood acute lymphoblastic leukemia.
      SH2B312q24.12Cell signaling and transductionHL/NHL
      • Shah S.
      • Schrader K.A.
      • Waanders E.
      • et al.
      A recurrent germline PAX5 mutation confers susceptibility to pre-B cell acute lymphoblastic leukemia.
      ,
      • Perez-Garcia A.
      • Ambesi-Impiombato A.
      • Hadler M.
      • et al.
      Genetic loss of SH2B3 in acute lymphoblastic leukemia.
      TP5317p13.1Tumor suppressorCLL
      • Levine A.J.
      • Momand J.
      • Finlay C.A.
      The p53 tumour suppressor gene.
      ,
      • Coltro G.
      • Lasho T.L.
      • Finke C.M.
      • et al.
      Germline SH2B3 pathogenic variant associated with myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis.
      ATM11q22.3Cell division and DNA repairAtaxia telangiectasia
      • Riaz I.B.
      • Faridi W.
      • Patnaik M.M.
      • Abraham R.S.
      A systematic review on predisposition to lymphoid (B and T cell) neoplasias in patients with primary immunodeficiencies and immune dysregulatory disorders (inborn errors of immunity).
      BLM15q26.1DNA helicaseBloom syndrome
      • Riaz I.B.
      • Faridi W.
      • Patnaik M.M.
      • Abraham R.S.
      A systematic review on predisposition to lymphoid (B and T cell) neoplasias in patients with primary immunodeficiencies and immune dysregulatory disorders (inborn errors of immunity).
      PTPN1112q24.13Regulation of RAS/MAPK signaling pathwayLeopard/Noonan syndrome
      • Riaz I.B.
      • Faridi W.
      • Patnaik M.M.
      • Abraham R.S.
      A systematic review on predisposition to lymphoid (B and T cell) neoplasias in patients with primary immunodeficiencies and immune dysregulatory disorders (inborn errors of immunity).
      NF117q11.2Encodes neurofibrominNeurofibromatosis (type 1)
      • Riaz I.B.
      • Faridi W.
      • Patnaik M.M.
      • Abraham R.S.
      A systematic review on predisposition to lymphoid (B and T cell) neoplasias in patients with primary immunodeficiencies and immune dysregulatory disorders (inborn errors of immunity).
      NBS18q21.3DNA repairNijmegen Breakage syndrome
      • Riaz I.B.
      • Faridi W.
      • Patnaik M.M.
      • Abraham R.S.
      A systematic review on predisposition to lymphoid (B and T cell) neoplasias in patients with primary immunodeficiencies and immune dysregulatory disorders (inborn errors of immunity).
      WASXp11.23Maintaining cellular structural frameworkWiskott-Aldrich syndrome
      • Riaz I.B.
      • Faridi W.
      • Patnaik M.M.
      • Abraham R.S.
      A systematic review on predisposition to lymphoid (B and T cell) neoplasias in patients with primary immunodeficiencies and immune dysregulatory disorders (inborn errors of immunity).
      BTKXq22.1Development and maturation of B cellsBruton agammaglobulinemia
      • Riaz I.B.
      • Faridi W.
      • Patnaik M.M.
      • Abraham R.S.
      A systematic review on predisposition to lymphoid (B and T cell) neoplasias in patients with primary immunodeficiencies and immune dysregulatory disorders (inborn errors of immunity).
      FAS10q23.31Cell signaling and apoptosisAutoimmune lymphoproliferative syndrome
      • Riaz I.B.
      • Faridi W.
      • Patnaik M.M.
      • Abraham R.S.
      A systematic review on predisposition to lymphoid (B and T cell) neoplasias in patients with primary immunodeficiencies and immune dysregulatory disorders (inborn errors of immunity).
      FASLG1q24.3Induction of apoptosis
      CASP102q33.1Execution-phase of apoptosis
      KLHDC8B (also 5’UTR region)3p21.31Protein-protein interactionsHodgkin lymphoma
      • Saarinen S.
      • Vahteristo P.
      • Launonen V.
      • et al.
      Analysis of KLHDC8B in familial nodular lymphocyte predominant Hodgkin lymphoma.
      Plasma cell neoplasms
      KDM1A/LSD11p36.12Histone demethylationMM, MGUS, WM
      • Wei X.
      • Calvo-Vidal M.N.
      • Chen S.
      • et al.
      Germline lysine-specific demethylase 1 (LSD1/KDM1A) mutations confer susceptibility to multiple myeloma.
      DIS313q22.1RNA processing
      • Pertesi M.
      • Vallee M.
      • Wei X.
      • et al.
      Exome sequencing identifies germline variants in DIS3 in familial multiple myeloma.
      Cancer predisposition syndromes
      TP5317p13.1Tumor suppressionLi-Fraumeni syndrome
      • Levine A.J.
      • Momand J.
      • Finlay C.A.
      The p53 tumour suppressor gene.
      MSH22p21-p16.3DNA mismatch repairLynch syndrome
      • Lynch H.T.
      • Snyder C.L.
      • Shaw T.G.
      • Heinen C.D.
      • Hitchins M.P.
      Milestones of Lynch syndrome: 1895-2015.
      MLH13p22.2
      MSH62p16.3
      PMS27p22.1
      ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; CLL = chronic lymphoblastic leukemia; CMML = chronic myelomonocytic leukemia; HL = Hodgkin lymphoma; JMML = juvenile myelomonocytic leukemia; MDS = myelodysplastic syndromes; MGUS = monoclonal gammopathy of undetermined significance; MM = multiple myeloma; MPN = myeloproliferative neoplasm; NHL = non-Hodgkin lymphoma; TMD = transient myeloproliferative disorder; WM = Waldenstrom macroglobulinemia.
      Owing to the large number of genes, only a select few have been incorporated in the table.

      Syndromic Familial Myeloid HPS

      Syndromic association of lymphedema and MDS/AML, known as Emberger syndrome, was found to result from alterations in GATA2 gene, which normally encodes a critical transcription factor essential for vascular development and hematopoietic stem-cell differentiation. Similarly, patients with monocytopenia and mycobacterial infections (MonoMAC) syndrome, and those with dendritic cell, monocyte, B and natural killer lymphoid deficiency, were found to harbor heterozygous variants in GATA2. Collectively, perturbations in the GATA2 gene are now categorized as “GATA2 haploinsufficiency syndrome,” and afflicted individuals are unified by a characteristic phenotypic variability and an increased tendency toward developing MDS and/or AML.
      • Ostergaard P.
      • Simpson M.A.
      • Connell F.C.
      • et al.
      Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome).
      Inherited defects in the nucleotide excision repair pathway are also associated with HPS. Patients with xeroderma pigmentosum, characterized by defects in nucleotide excision repair (XPC delTG germline variants) were found to have an increased predisposition toward developing Tp53/complex karyotype MDS and AML.
      • Coltro G.
      • Lasho T.L.
      • Finke C.M.
      • et al.
      Germline SH2B3 pathogenic variant associated with myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis.
      In 2016, a new syndrome of myelodysplasia, infection, growth restriction, adrenal hypoplasia, genital abnormalities, and enteropathy (also known as MIRAGE syndrome) was identified among 11 patients and found to be caused by germline-activating heterozygous variants in the SAMD9 gene. Similarly, missense variants in a paralog of SAMD9, known as SAMD9L, were found to be associated with ataxia-pancytopenia syndrome. Biologically, both these genes have a role in endosomal fusion, and SAMD9 regulates growth factor signal transduction.
      • Narumi S.
      • Amano N.
      • Ishii T.
      • et al.
      SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7.
      It is interesting that loss of chromosome 7 was the most common genetic event heralding the onset of MDS, likely as an adaptation mechanism to the growth-restrictive effects from mutant SAMD9 protein.
      • Schwartz J.R.
      • Wang S.
      • Ma J.
      • et al.
      Germline SAMD9 mutation in siblings with monosomy 7 and myelodysplastic syndrome.
      ,
      • Maciaszek J.L.
      • Oak N.
      • Chen W.
      • et al.
      Enrichment of heterozygous germline RECQL4 loss-of-function variants in pediatric osteosarcoma.
      Heterozygous variants in DNA helicase genes—in particular, RECQL4—have been associated with AML.
      • Stieglitz E.
      • Loh M.L.
      Genetic predispositions to childhood leukemia.
      Germline variants in this gene have been implicated in causing a defined syndrome characterized by dermatosis, short stature, juvenile cataracts, skeletal abnormalities, radial ray defects, premature aging, and predisposition to malignancies such as osteosarcoma, lymphoma, and AML, also known as Rothmund-Thomson syndrome.
      • Ghosh A.K.
      • Rossi M.L.
      • Singh D.K.
      • et al.
      RECQL4, the protein mutated in Rothmund-Thomson syndrome, functions in telomere maintenance.
      ,
      • Tartaglia M.
      • Martinelli S.
      • Cazzaniga G.
      • et al.
      Genetic evidence for lineage-related and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia.
      Genomic signatures that define the predisposing clinical syndromes can sometimes point toward the type of myeloid neoplasms that may develop later. Specific examples include germline variants activating the RAS-MAP kinase pathway in genes, PTPN11 (Noonan syndrome) and CBL, which increase predisposition to develop myeloid neoplasms primarily genomically dominated by RAS pathway variants (juvenile myelomonocytic leukemia [JMML], CMML)
      • Martinelli S.
      • Stellacci E.
      • Pannone L.
      • et al.
      Molecular diversity and associated Phenotypic spectrum of germline CBL mutations.
      • Muraoka M.
      • Okuma C.
      • Kanamitsu K.
      • et al.
      Adults with germline CBL mutation complicated with juvenile myelomonocytic leukemia at infancy.
      • Kirwan M.
      • Walne A.J.
      • Plagnol V.
      • et al.
      Exome sequencing identifies autosomal-dominant SRP72 mutations associated with familial aplasia and myelodysplasia.
      (Table 1).

      Familial Predisposition to Myeloproliferative Neoplasms

      Evidence of a familial predisposition for myeloproliferative neoplasms (MPNs) was apparent when single nucleotide polymorphisms within the JAK2 (46/1 haplotype) gene were shown to predispose to MPN.
      • Pardanani A.
      • Fridley B.L.
      • Lasho T.L.
      • Gilliland D.G.
      • Tefferi A.
      Host genetic variation contributes to phenotypic diversity in myeloproliferative disorders.
      • Pardanani A.
      • Lasho T.
      • McClure R.
      • Lacy M.
      • Tefferi A.
      Discordant distribution of JAK2V617F mutation in siblings with familial myeloproliferative disorders.
      • Jones A.V.
      • Chase A.
      • Silver R.T.
      • et al.
      JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms.
      • Kilpivaara O.
      • Mukherjee S.
      • Schram A.M.
      • et al.
      A germline JAK2 SNP is associated with predisposition to the development of JAK2(V617F)-positive myeloproliferative neoplasms.
      • Hinds D.A.
      • Barnholt K.E.
      • Mesa R.A.
      • et al.
      Germ line variants predispose to both JAK2 V617F clonal hematopoiesis and myeloproliferative neoplasms.
      Subsequently, in 4 genetically related families, germline duplication of a 700-kilo base containing region of chromosome 14q32 containing 5 protein coding genes—TCL1A, ATG2B, GSKIP, BDKRB1, and BDKRB2—were found to cooperate with acquired JAK2, MPL, and CALR mutations in inducing disease by conferring a fitness advantage to cells carrying these mutations and resulting in a highly penetrant MPN phenotype.
      • Gripp K.W.
      • Curry C.
      • Olney A.H.
      • et al.
      Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28.
      Substantive correlative studies narrowed down the pathogenicity to ATG2B and GSKIP genes; however, this conclusion has been contested by the report of a family with germline duplication of chromosome 14q32 without involving the ATG2B and GSKIP genes.
      • Saliba J.
      • Saint-Martin C.
      • Di Stefano A.
      • et al.
      Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies.
      Other germline variants shown to predispose to development of MPNs include RBBP6
      • Harutyunyan A.S.
      • Giambruno R.
      • Krendl C.
      • et al.
      Germline RBBP6 mutations in familial myeloproliferative neoplasms.
      and SH2B3.
      • Rumi E.
      • Cazzola M.
      Advances in understanding the pathogenesis of familial myeloproliferative neoplasms.
      Single nucleotide polymorphisms in TERT, SH2B3, MECOM, HBS1L, MYB, TET2, ATM, CHEK2, LINC-PINT, and GF1B genes have also been associated in families with MPN clustering.
      • Sanders M.A.
      • Chew E.
      • Flensburg C.
      • et al.
      MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML.
      ,
      • Beel K.
      • Vandenberghe P.
      G-CSF receptor (CSF3R) mutations in X-linked neutropenia evolving to acute myeloid leukemia or myelodysplasia.
      ,
      • Perez-Garcia A.
      • Ambesi-Impiombato A.
      • Hadler M.
      • et al.
      Genetic loss of SH2B3 in acute lymphoblastic leukemia.
      ,
      • Rumi E.
      • Cazzola M.
      Advances in understanding the pathogenesis of familial myeloproliferative neoplasms.
      ,
      • Germeshausen M.
      • Ancliff P.
      • Estrada J.
      • et al.
      MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia.
      However, it is also relevant to note that despite familial clustering of MPNs, a clear predisposition gene cannot be found, highlighting limitations of current technology and knowledge.

      Nonsyndromic Familial Myeloid Predisposition Syndromes

      This group of HMMS do not present with any characteristic syndrome or clinical features. Germline variant in the gene, CEBPA, which encodes CEBPAα, has been associated with MDS/AML.
      • Smith M.L.
      • Cavenagh J.D.
      • Lister T.A.
      • Fitzgibbon J.
      Mutation of CEBPA in familial acute myeloid leukemia.
      This was followed by the discovery that patients with germline pathogenic variants in the DEAD/H-box helicase gene, DDX41 gene, were predisposed to somatic DDX41 variants as a second hit, with the consequent development of high-risk MDS/AML.
      • Polprasert C.
      • Schulze I.
      • Sekeres M.A.
      • et al.
      Inherited and somatic defects in DDX41 in myeloid neoplasms.
      In addition, DDX41 expression was found to be haploinsufficient in patients with deletion 5q involving the DDX41 locus and associated with responses to lenalidomide, highlighting important therapeutic implications.
      • Polprasert C.
      • Schulze I.
      • Sekeres M.A.
      • et al.
      Inherited and somatic defects in DDX41 in myeloid neoplasms.
      ,
      • Vairo F.P.E.
      • Ferrer A.
      • Cathcart-Rake E.
      • et al.
      Novel germline missense DDX41 variant in a patient with an adult-onset myeloid neoplasm with excess blasts without dysplasia.
      Similarly, biallelic germline pathogenic variants in ERCC6L2 have been shown to increase predisposition to AML,
      • Douglas S.P.M.
      • Siipola P.
      • Kovanen P.E.
      • et al.
      ERCC6L2 defines a novel entity within inherited acute myeloid leukemia.
      and exome and single-nucleotide polymorphism haplotype analysis have also identified SRP72 pathogenic variant in a family with aplastic anemia (AA) and MDS.
      • Sarasin A.
      • Quentin S.
      • Droin N.
      • et al.
      Familial predisposition to TP53/complex karyotype MDS and leukemia in DNA repair-deficient xeroderma pigmentosum.
      Recently, germline pathogenic variants in the MBD4 gene, which functions to repair spontaneous deamination-induced methylation damage via the base excision pathway, were found to be associated with early-onset AML, through acquisition of mutant driver genes, most notably DNMT3A.
      • Nagamachi A.
      • Matsui H.
      • Asou H.
      • et al.
      Haploinsufficiency of SAMD9L, an endosome fusion facilitator, causes myeloid malignancies in mice mimicking human diseases with monosomy 7.
      Additional details are in Table 1.

      Inherited Bone Marrow-Failure Syndromes With Predisposition to Myeloid Neoplasms

      Beyond these specific genomically defined HMMS, patients with inherited bone marrow failure also have an increased cumulative incidence of MDS and AML.
      • Mangaonkar A.A.
      • Patnaik M.M.
      Short telomere syndromes in clinical practice: bridging bench and bedside.
      Complementation groups of Fanconi anemia have a well-established association with MDS/AML,
      • Alter B.P.
      • Giri N.
      • Savage S.A.
      • Rosenberg P.S.
      Cancer in the National Cancer Institute inherited bone marrow failure syndrome cohort after fifteen years of follow-up.
      which is characterized by presence of a specific pattern of unbalanced chromosomal translocations and partial chromosome arm duplications or deletions (including a cryptic RUNX1/AML1 fusion) and virtual absence of classical de novo translocations such as t(8;21), t(15;17) and MLL.
      • Quentin S.
      • Cuccuini W.
      • Ceccaldi R.
      • et al.
      Myelodysplasia and leukemia of Fanconi anemia are associated with a specific pattern of genomic abnormalities that includes cryptic RUNX1/AML1 lesions.
      Biallelic germline pathogenic variants in the 22 FANC genes (except FANCB and FANCR) are associated with AML.
      • Maung K.Z.Y.
      • Leo P.J.
      • Bassal M.
      • et al.
      Rare variants in Fanconi anemia genes are enriched in acute myeloid leukemia.
      Inherited bone marrow-failure syndromes grouped by gene variants affecting telomere structure and function, also known as short telomere syndrome (STS), display a wide spectrum of phenotypic diversity (premature graying of hair, idiopathic pulmonary fibrosis, immune dysregulation, and/or cryptogenic cirrhosis) and are characterized by increased predisposition toward MDS/AML.
      • Oddsson A.
      • Kristinsson S.Y.
      • Helgason H.
      • et al.
      The germline sequence variant rs2736100_C in TERT associates with myeloproliferative neoplasms.
      ,
      • Mangaonkar A.A.
      • Ferrer A.
      • Pinto E.V.F.
      • et al.
      Clinical correlates and treatment outcomes for patients with short telomere syndromes.
      ,
      • Armanios M.
      Telomerase mutations and the pulmonary fibrosis-bone marrow failure syndrome complex.
      • Armanios M.
      Telomerase and idiopathic pulmonary fibrosis.
      • Armanios M.
      • Blackburn E.H.
      The telomere syndromes.
      Specifically among STS genes, thus far only TERT, TERC, and RTEL1 have been associated with myeloid neoplasms.
      • Townsley D.M.
      • Dumitriu B.
      • Young N.S.
      Bone marrow failure and the telomeropathies.
      ,
      • Oddsson A.
      • Kristinsson S.Y.
      • Helgason H.
      • et al.
      The germline sequence variant rs2736100_C in TERT associates with myeloproliferative neoplasms.
      ,
      • Armanios M.
      • Blackburn E.H.
      The telomere syndromes.
      ,
      • Marsh J.C.W.
      • Gutierrez-Rodrigues F.
      • Cooper J.
      • et al.
      Heterozygous RTEL1 variants in bone marrow failure and myeloid neoplasms.
      Germline variants in the POT1 gene, which is part of the Shelterin complex and functions to protect the structural integrity of telomeres, is also associated with increased incidence of several cancers such as familial CLL, colorectal carcinoma, angiosarcoma, glioma, and malignant melanoma, also called “long telomere syndromes,” owing to a pathological mechanism of telomere maintenance and elongation.
      • Calvete O.
      • Garcia-Pavia P.
      • Dominguez F.
      • et al.
      The wide spectrum of POT1 gene variants correlates with multiple cancer types.
      • Speedy H.E.
      • Kinnersley B.
      • Chubb D.
      • et al.
      Germ line mutations in shelterin complex genes are associated with familial chronic lymphocytic leukemia.
      • Stanley S.E.
      • Armanios M.
      The short and long telomere syndromes: paired paradigms for molecular medicine.
      • McNally E.J.
      • Luncsford P.J.
      • Armanios M.
      Long telomeres and cancer risk: the price of cellular immortality.
      As iterated before, GATA2 haploinsufficiency syndrome is now considered a genomically defined germline bone marrow-failure syndrome, with an increased predisposition to develop myeloid leukemias.
      • Kazenwadel J.
      • Secker G.A.
      • Liu Y.J.
      • et al.
      Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature.
      ,
      • Zhang S.J.
      • Ma L.Y.
      • Huang Q.H.
      • et al.
      Gain-of-function mutation of GATA-2 in acute myeloid transformation of chronic myeloid leukemia.
      Specific morphologic, immunophenotypic, and cytogenetic features distinguish GATA2-related bone marrow failure from idiopathic AA, such as presence of greater overall cellularity, increased atypical megakaryocytes, reduced monocytes, mature B and NK cells, increased atypical plasma cells (in a subset of GATA2 patients), and abnormal cytogenetics (in >50% GATA2 patients) with common abnormalities including trisomy 8, monosomy 7, and deletion 7q.
      • Ganapathi K.A.
      • Townsley D.M.
      • Hsu A.P.
      • et al.
      GATA2 deficiency-associated bone marrow disorder differs from idiopathic aplastic anemia.
      Specific genotypic correlations are observed in germline GATA2-related AML such as predominance of pathogenic variants in the second zinc finger domain of GATA2 and acquisition of somatic “second-hit” variants in ASXL1 and FLT3L genes heralding the development of AML.
      • Zhang S.J.
      • Ma L.Y.
      • Huang Q.H.
      • et al.
      Gain-of-function mutation of GATA-2 in acute myeloid transformation of chronic myeloid leukemia.
      ,
      • Mir M.A.
      • Kochuparambil S.T.
      • Abraham R.S.
      • et al.
      Spectrum of myeloid neoplasms and immune deficiency associated with germline GATA2 mutations.
      ,
      • West R.R.
      • Hsu A.P.
      • Holland S.M.
      • Cuellar-Rodriguez J.
      • Hickstein D.D.
      Acquired ASXL1 mutations are common in patients with inherited GATA2 mutations and correlate with myeloid transformation.
      Mechanistic cooperation of GATA2 gene with the aforementioned somatic variants needs further exploration. Shwachman-Diamond syndrome is an autosomal recessive inherited bone marrow-failure syndrome (IBMFS) caused by pathogenic variants in the SBDS gene (>90% patients) affecting ribosome biogenesis and clinically characterized by skeletal and neurodevelopmental abnormalities, exocrine pancreatic insufficiency, and bone marrow failure with increased predisposition toward development of MDS and/or AML.
      • Dror Y.
      Shwachman-Diamond syndrome.
      Specific chromosomal abnormalities include interstitial deletion of long arm of chromosome 20 and isochromosome of long arm of chromosome 7.
      • Valli R.
      • Minelli A.
      • Galbiati M.
      • et al.
      Shwachman-Diamond syndrome with clonal interstitial deletion of the long arm of chromosome 20 in bone marrow: haematological features, prognosis and genomic instability.
      ,
      • Aziz A.
      • Baxter E.J.
      • Edwards C.
      • et al.
      Cooperativity of imprinted genes inactivated by acquired chromosome 20q deletions.
      Clonal interstitial deletion of the long arm of chromosome 20 is thought to confer a better prognosis and is genomically characterized by the loss of EIF6.
      • Valli R.
      • Minelli A.
      • Galbiati M.
      • et al.
      Shwachman-Diamond syndrome with clonal interstitial deletion of the long arm of chromosome 20 in bone marrow: haematological features, prognosis and genomic instability.
      In a small proportion of patients, biallelic variants in 2 other genes, DNAJC21 and EFL1, may also cause a Shwachman-Diamond syndrome-like condition.
      • Boocock G.R.
      • Morrison J.A.
      • Popovic M.
      • et al.
      Mutations in SBDS are associated with Shwachman-Diamond syndrome.
      • Dhanraj S.
      • Matveev A.
      • Li H.
      • et al.
      Biallelic mutations in DNAJC21 cause Shwachman-Diamond syndrome.
      • D'Amours G.
      • Lopes F.
      • Gauthier J.
      • et al.
      Refining the phenotype associated with biallelic DNAJC21 mutations.
      Diamond-Blackfan anemia (DBA) is an IBMFS classified as a ribosomal disorder characterized by red cell aplasia, congenital abnormalities (craniofacial anomalies such as cute snub nose and wide-spaced eyes and upper-extremity anomalies such as radial abnormalities including hypoplastic thumbs, genitourinary and cardiac anomalies such as atrial and/or ventricular septal defect and coarctation of aorta), and increased predisposition toward developing MDS/AML and osteogenic sarcoma.
      • Mangaonkar A.A.
      • Patnaik M.M.
      Short telomere syndromes in clinical practice: bridging bench and bedside.
      ,
      • Stepensky P.
      • Chacon-Flores M.
      • Kim K.H.
      • et al.
      Mutations in EFL1, an SBDS partner, are associated with infantile pancytopenia, exocrine pancreatic insufficiency and skeletal anomalies in aShwachman-Diamond like syndrome.
      In approximately 70% cases with a DBA phenotype, causative variants include RPS19, RPS24, RPS17, RPL5, RPL11, and RPL35A, all inherited in an autosomal dominant pattern and with an impact on ribosomal biogenesis.
      • Mangaonkar A.A.
      • Patnaik M.M.
      Short telomere syndromes in clinical practice: bridging bench and bedside.
      ,
      • Lipton J.M.
      • Ellis S.R.
      Diamond-Blackfan anemia: diagnosis, treatment, and molecular pathogenesis.
      Of note, among this group of HPS, there are specific genotype-phenotype correlations such as association of craniofacial abnormalities with RPL5 (which binds with TCOF1).
      • Stepensky P.
      • Chacon-Flores M.
      • Kim K.H.
      • et al.
      Mutations in EFL1, an SBDS partner, are associated with infantile pancytopenia, exocrine pancreatic insufficiency and skeletal anomalies in aShwachman-Diamond like syndrome.
      Typical laboratory clues to identification of DBA include presentation of anemia before the first birthday, reticulocytopenia, macrocytosis, increased fetal hemoglobin levels, and elevation of erythrocyte adenosine deaminase enzyme (to be assessed before red blood cell transfusion dependence).
      • Stepensky P.
      • Chacon-Flores M.
      • Kim K.H.
      • et al.
      Mutations in EFL1, an SBDS partner, are associated with infantile pancytopenia, exocrine pancreatic insufficiency and skeletal anomalies in aShwachman-Diamond like syndrome.
      In a large DBA registry, the incidence of AML/MDS was reported to be approximately 1% (6 of 608 patients) after a prolonged follow-up.
      • Ulirsch J.C.
      • Verboon J.M.
      • Kazerounian S.
      • et al.
      The genetic landscape of Diamond-Blackfan anemia.
      However, mechanistic biology of clonal evolution in this disease is still not clear. DBA-like phenotype can also occur as a consequence of loss of function GATA1 variants,
      • Vlachos A.
      • Rosenberg P.S.
      • Atsidaftos E.
      • Alter B.P.
      • Lipton J.M.
      Incidence of neoplasia in Diamond-Blackfan anemia: a report from the Diamond-Blackfan Anemia Registry.
      • Sankaran V.G.
      • Ghazvinian R.
      • Do R.
      • et al.
      Exome sequencing identifies GATA1 mutations resulting in Diamond-Blackfan anemia.
      • Ludwig L.S.
      • Gazda H.T.
      • Eng J.C.
      • et al.
      Altered translation of GATA1 in Diamond-Blackfan anemia.
      ,
      • Parrella S.
      • Aspesi A.
      • Quarello P.
      • et al.
      Loss of GATA-1 full length as a cause of Diamond-Blackfan anemia phenotype.
      biallelic ADA2 variants resulting in a deficiency of adenosine deaminase-2,
      • Zhou Q.
      • Yang D.
      • Ombrello A.K.
      • et al.
      Early-onset stroke and vasculopathy associated with mutations in ADA2.
      and TSR2 variants, also associated with mandibulofacial dysostosis.
      • Klar J.
      • Khalfallah A.
      • Arzoo P.S.
      • Gazda H.T.
      • Dahl N.
      Recurrent GATA1 mutations in Diamond-Blackfan anaemia.
      Severe congenital neutropenia (SCN) is a heterogeneous group of disorders responsible for neutropenia at or near birth, only a fraction of which are due to inherited or germline variants. Based on the presence or absence of specific clinical features, they can grouped into the following categories:

      SCN without extrahematopoietic abnormalities or primary immunodeficiency

      This group includes patients with SCN and pathogenic variants in the ELANE gene,
      • Ballmaier M.
      • Germeshausen M.
      • Schulze H.
      • et al.
      c-mpl mutations are the cause of congenital amegakaryocytic thrombocytopenia.
      which encodes for neutrophil elastase and is inherited as an autosomal dominant disorder, and those with germline variants in the G-CSF receptor (CSF3R, which may also result in nonresponsiveness to granulocyte growth factor therapy).
      • Dong F.
      • Brynes R.K.
      • Tidow N.
      • Welte K.
      • Lowenberg B.
      • Touw I.P.
      Mutations in the gene for the granulocyte colony-stimulating-factor receptor in patients with acute myeloid leukemia preceded by severe congenital neutropenia.
      ,
      • Dong F.
      • Hoefsloot L.H.
      • Schelen A.M.
      • et al.
      Identification of a nonsense mutation in the granulocyte-colony-stimulating factor receptor in severe congenital neutropenia.

      SCN without extrahematopoietic abnormalities but with primary immunodeficiency

      This group includes SCN patients with loss-of-function CXCR2 and gain-of-function CXCR4 variants (associated with warts; hypogammaglobulinemia, immunodeficiency; and myelokathexis syndrome, also known as WHIM syndrome),
      • Eash K.J.
      • Greenbaum A.M.
      • Gopalan P.K.
      • Link D.C.
      CXCR2 and CXCR4 antagonistically regulate neutrophil trafficking from murine bone marrow.
      Wiskott Aldrich Syndrome (X-linked disorder associated with microthrombocytopenia, eczema, and recurrent infections),
      • Kawai T.
      • Choi U.
      • Cardwell L.
      • et al.
      WHIM syndrome myelokathexis reproduced in the NOD/SCID mouse xenotransplant model engrafted with healthy human stem cells transduced with C-terminus-truncated CXCR4.
      CD40LG (decreased IgM response), GFI1 germline variants (also associated with lymphopenia),
      • Person R.E.
      • Li F.Q.
      • Duan Z.
      • et al.
      Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2.
      and STK4 (T- and B-cell deficiency) gene abonormalities.
      • Abdollahpour H.
      • Appaswamy G.
      • Kotlarz D.
      • et al.
      The phenotype of human STK4 deficiency.

      SCN with extrahematopoietic abnormalities

      Patients with SCN and variants in genes, HAX1 (neurologic manifestations such as developmental delay and seizures),
      • Boxer L.A.
      • Stein S.
      • Buckley D.
      • Bolyard A.A.
      • Dale D.C.
      Strong evidence for autosomal dominant inheritance of severe congenital neutropenia associated with ELA2 mutations.
      G6PC3 (Dursun syndrome characterized by prominent superficial venous pattern, urogenital and congenital cardiac defects, intermittent thrombocytopenia, and pulmonary hypertension),
      • McDermott D.H.
      • De Ravin S.S.
      • Jun H.S.
      • et al.
      Severe congenital neutropenia resulting from G6PC3 deficiency with increased neutrophil CXCR4 expression and myelokathexis.
      TAZ (Barth syndrome, manifesting as short stature, cardiac and skeletal myopathy),
      • Bione S.
      • D'Adamo P.
      • Maestrini E.
      • Gedeon A.K.
      • Bolhuis P.A.
      • Toniolo D.
      A novel X-linked gene, G4.5. is responsible for Barth syndrome.
      LYST (Chédiak-Hegashi syndrome, manifesting as hypopigmentation, neuropathy, immunodeficiency, and hemophagocytic lymphohistiocytosis), AP3B1 (Type 2 Hermansky-Pudlak syndrome), and AP14 (albinism),
      • Huizing M.
      • Scher C.D.
      • Strovel E.
      • et al.
      Nonsense mutations in ADTB3A cause complete deficiency of the beta3A subunit of adaptor complex-3 and severe Hermansky-Pudlak syndrome type 2.
      SBDS (aforementioned Shwachman Diamond syndrome),
      • Shimamura A.
      • Alter B.P.
      Pathophysiology and management of inherited bone marrow failure syndromes.
      C16orf57 (Clericuzio poikiloderma),
      • Mostefai R.
      • Morice-Picard F.
      • Boralevi F.
      • et al.
      Poikiloderma with neutropenia, Clericuzio type, in a family from Morocco.
      SLC37A4 (glycogen storage defect causing hypoglycemia, glycogen overload in liver), VPS13B (Cohen syndrome, manifesting as intellectual deficiency, microcephaly, facial abnormalities, joint laxity, hypotonia, truncal obesity, chorioretinal dystrophy, and myopia),
      • Gueneau L.
      • Duplomb L.
      • Sarda P.
      • et al.
      Congenital neutropenia with retinopathy, a new phenotype without intellectual deficiency or obesity secondary to VPS13B mutations.
      VPS45 (nephromegaly, splenomegaly, primary myelofibrosis of infancy, neurological abnormalities),
      • Stepensky P.
      • Saada A.
      • Cowan M.
      • et al.
      The Thr224Asn mutation in the VPS45 gene is associated with the congenital neutropenia and primary myelofibrosis of infancy.
      TCIRG1 (prominent hemangiomas),
      • Makaryan V.
      • Rosenthal E.A.
      • Bolyard A.A.
      • et al.
      TCIRG1-associated congenital neutropenia.
      JAGN1 (short stature, bone and teeth defects),
      • Boztug K.
      • Jarvinen P.M.
      • Salzer E.
      • et al.
      JAGN1 deficiency causes aberrant myeloid cell homeostasis and congenital neutropenia.
      CLPB (3-methyglutaco-nic aciduria type VII),
      • Wortmann S.B.
      • Zietkiewicz S.
      • Kousi M.
      • et al.
      CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.
      TCN2 (vitamin B12 deficiency),
      • Skokowa J.
      • Dale D.C.
      • Touw I.P.
      • Zeidler C.
      • Welte K.
      Severe congenital neutropenias.
      EIF2AK3 (diabetes mellitus, skeletal dysplasia, stunted growth),
      • Ozbek M.N.
      • Senee V.
      • Aydemir S.
      • et al.
      Wolcott-Rallison syndrome due to the same mutation (W522X) in EIF2AK3 in two unrelated families and review of the literature.
      DNM2 (Charcot-Marie Tooth disease presenting as limb weakness and atrophy),
      • Liewluck T.
      • Lovell T.L.
      • Bite A.V.
      • Engel A.G.
      Sporadic centronuclear myopathy with muscle pseudohypertrophy, neutropenia, and necklace fibers due to a DNM2 mutation.
      RAB27A (hypopigmentation, immunodeficiency, and hemophagocytic lymphohistiocytosis, also known as type 2 Griscelli syndrome),
      • Kawakami T.
      • He J.
      • Morita H.
      • et al.
      Rab27a is essential for the formation of neutrophil extracellular traps (NETs) in neutrophil-like differentiated HL60 cells.
      CTSC (hyperkeratosis and periodontitis),
      • Sorensen O.E.
      • Clemmensen S.N.
      • Dahl S.L.
      • et al.
      Papillon-Lefevre syndrome patient reveals species-dependent requirements for neutrophil defenses.
      and LAMTOR2 and RAB27A (skin manifestations)
      • Bohn G.
      • Allroth A.
      • Brandes G.
      • et al.
      A novel human primary immunodeficiency syndrome caused by deficiency of the endosomal adaptor protein p14.
      ,
      • Menasche G.
      • Pastural E.
      • Feldmann J.
      • et al.
      Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome.
      belong in this group. Although more than 100 pathogenic variants have been associated with SCN, in approximately 25% patients, no causative variant is found. Further, literature on a definitive association with increased predisposition to develop MDS/AML is only available for a handful of SCN genes: namely, ELANE, HAX1, WAS, and CSF3R.
      • Matsubara K.
      • Imai K.
      • Okada S.
      • et al.
      Severe developmental delay and epilepsy in a Japanese patient with severe congenital neutropenia due to HAX1 deficiency.
      Classic bone marrow findings include maturation arrest at the promyelocyte/myelocyte stage of development, with atypical nuclei and cytoplasmic vacuolization. A large registry report of 374 well-characterized patients with SCN on long-term (10 years) granulyte-colony stimulating factor (G-CSF) therapy suggested an annual risk of MDS/AML to be about 2.3% per year, and after 15 years on G-CSF therapy, rate of death from sepsis was approximately 10%, whereas MDS/AML was approximately 22%.
      • Rosenberg P.S.
      • Zeidler C.
      • Bolyard A.A.
      • et al.
      Stable long-term risk of leukaemia in patients with severe congenital neutropenia maintained on G-CSF therapy.
      Some reports imply that acquisition of G-CSF receptor variants signal the onset of MDS/AML in these patients.
      • Touw I.P.
      Game of clones: the genomic evolution of severe congenital neutropenia.
      ,
      • Beekman R.
      • Touw I.P.
      G-CSF and its receptor in myeloid malignancy.
      Thrombocytopenia absent radii (TAR) syndrome and congenital amegakaryocytic thrombocytopenia (CAMT) are 2 important hereditary causes of thrombocytopenia. TAR syndrome is a rare congenital disorder characterized by bilateral radius aplasia and thrombocytopenia and caused by a chromosome 1 microdeletion including the RBM8A gene or a single nucleotide polymorphism within the 5’-UTR or first intron of the RMB8A gene.
      • Albers C.A.
      • Paul D.S.
      • Schulze H.
      • et al.
      Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome.
      CAMT is caused by alterations in the gene for the thrombopoietin receptor, c-Mpl, resulting in high levels of serum thrombopoietin.
      • Tapper W.
      • Jones A.V.
      • Kralovics R.
      • et al.
      Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms.
      There have only been a few case reports of CAMT and TAR that have evolved to AML.
      • Mangaonkar A.A.
      • Patnaik M.M.
      Short telomere syndromes in clinical practice: bridging bench and bedside.

      Lymphoid Neoplasms

      Clinical studies including twin, case-control, cohort, and registry-based studies have shown that first-degree relatives of patients with CLL, non-Hodgkin lymphoma (NHL), and Hodgkin lymphoma (HL) have ~8.5, 1.7, and 3.1 times the rate of developing the same lymphoid malignancy.
      • Cerhan J.R.
      • Slager S.L.
      Familial predisposition and genetic risk factors for lymphoma.
      Following these clinical observations, Genome-Wide Association Studies have identified several genetic susceptibilities for these cancers
      • Crowther-Swanepoel D.
      • Broderick P.
      • Di Bernardo M.C.
      • et al.
      Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk.
      • Speedy H.E.
      • Di Bernardo M.C.
      • Sava G.P.
      • et al.
      A genome-wide association study identifies multiple susceptibility loci for chronic lymphocytic leukemia.
      • Slager S.L.
      • Rabe K.G.
      • Achenbach S.J.
      • et al.
      Genome-wide association study identifies a novel susceptibility locus at 6p21.3 among familial CLL.
      • Slager S.L.
      • Skibola C.F.
      • Di Bernardo M.C.
      • et al.
      Common variation at 6p21.31 (BAK1) influences the risk of chronic lymphocytic leukemia.
      • Skibola C.F.
      • Berndt S.I.
      • Vijai J.
      • et al.
      Genome-wide association study identifies five susceptibility loci for follicular lymphoma outside the HLA region.
      • Law P.J.
      • Berndt S.I.
      • Speedy H.E.
      • et al.
      Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia.
      • Di Bernardo M.C.
      • Crowther-Swanepoel D.
      • Broderick P.
      • et al.
      A genome-wide association study identifies six susceptibility loci for chronic lymphocytic leukemia.
      but definite familial predisposition is only attributed to select genes (Table 1).
      Inherited pathogenic variant of lymphoid transcription factor, PAX5 (also called BSAP), accompanied by loss of heterozygosity and retention of a mutant allele at chromosome 9p13, was shown to be associated with familial B-ALL.
      • Churchman M.L.
      • Qian M.
      • Te Kronnie G.
      • et al.
      Germline genetic IKZF1 variation and predisposition to childhood acute lymphoblastic leukemia.
      Similarly, germline homozygous variants in a negative regulator of cytokine signaling, SH2 adaptor protein 3 (SH2B3) and a lymphoid transcription factor, IKAROS (IKZF1) are associated with B-ALL.
      • Labuhn M.
      • Perkins K.
      • Matzk S.
      • et al.
      Mechanisms of progression of myeloid preleukemia to transformed myeloid leukemia in children with Down syndrome.
      ,
      • Shah S.
      • Schrader K.A.
      • Waanders E.
      • et al.
      A recurrent germline PAX5 mutation confers susceptibility to pre-B cell acute lymphoblastic leukemia.
      As mentioned earlier, the POT1 gene, part of the shelterin complex of telomeres, has been associated with familial CLL (among other cancers).
      • Speedy H.E.
      • Kinnersley B.
      • Chubb D.
      • et al.
      Germ line mutations in shelterin complex genes are associated with familial chronic lymphocytic leukemia.
      Reciprocal translocation and 5’-UTR polymorphisms in the gene-encoding midbody kelch protein (KLHDC8B) have been associated classical and nodular lymphocyte predominant Hodgkin lymphoma.
      • Saarinen S.
      • Vahteristo P.
      • Launonen V.
      • et al.
      Analysis of KLHDC8B in familial nodular lymphocyte predominant Hodgkin lymphoma.
      ,
      • Salipante S.J.
      • Mealiffe M.E.
      • Wechsler J.
      • et al.
      Mutations in a gene encoding a midbody kelch protein in familial and sporadic classical Hodgkin lymphoma lead to binucleated cells.
      Specific inherited immune deficiency syndromes—such as ataxia telangiectasia (ATM), Bloom syndrome (BLM), Wiskott Aldrich syndrome (WAS), Nijmegen Breakage syndrome (NBS1), cartilage hair hypoplasia (RMRP), adenosine deaminase 1 deficiency (ADA1), Bruton agammaglobulinemia (BTK), and many others—are also associated with an increased risk of B- and T-cell lymphomas.
      • Riaz I.B.
      • Faridi W.
      • Patnaik M.M.
      • Abraham R.S.
      A systematic review on predisposition to lymphoid (B and T cell) neoplasias in patients with primary immunodeficiencies and immune dysregulatory disorders (inborn errors of immunity).
      Cartilage hair hypoplasia is especially unique as it has some degree of phenotypic overlap with dyskeratosis congenita (DKC), is associated with critically shortened lymphocyte telomere length secondary to a perturbed telomere homeostasis, significant immunodeficiency and predisposition to lymphoid neoplasms.
      • Aubert G.
      • Strauss K.A.
      • Lansdorp P.M.
      • Rider N.L.
      Defects in lymphocyte telomere homeostasis contribute to cellular immune phenotype in patients with cartilage-hair hypoplasia.
      ,
      • Makitie O.
      • Pukkala E.
      • Teppo L.
      • Kaitila I.
      Increased incidence of cancer in patients with cartilage-hair hypoplasia.
      Among B-cell lymphomas in patients with primary immunodeficiency and immune dysregulatory disorders, a meta-analysis has shown a frequency of 37% for unspecified NHL, 15% for diffuse large B-cell lymphoma, 13% for HL, 5% for HL and marginal zone lymphoma, 4% for Burkitt lymphoma, and 0.4% for diffuse histiocytic lymphoma, respectively.
      • Riaz I.B.
      • Faridi W.
      • Patnaik M.M.
      • Abraham R.S.
      A systematic review on predisposition to lymphoid (B and T cell) neoplasias in patients with primary immunodeficiencies and immune dysregulatory disorders (inborn errors of immunity).
      Although the biological mechanism for neoplastic transformation is unclear, an intrinsic susceptibility to DNA damage and excess antigenic stimulation due to repeated infections in the setting of impaired immune checkpoints and antitumor surveillance could explain the increased predisposition for cancer in these disorders. Cellular pathway involving DNA double-strand break repair, which uses nonhomologous end joining and homology-directed recombination, is of particular relevance in the context of monogenic immune system defects and predisposition to hematopoietic neoplasms.
      • Riaz I.B.
      • Faridi W.
      • Patnaik M.M.
      • Abraham R.S.
      A systematic review on predisposition to lymphoid (B and T cell) neoplasias in patients with primary immunodeficiencies and immune dysregulatory disorders (inborn errors of immunity).
      Specific associations are highlighted in Table 1 and reviewed extensively elsewhere.
      • Riaz I.B.
      • Faridi W.
      • Patnaik M.M.
      • Abraham R.S.
      A systematic review on predisposition to lymphoid (B and T cell) neoplasias in patients with primary immunodeficiencies and immune dysregulatory disorders (inborn errors of immunity).
      It is important to note that several monogenic DNA repair defects associated with cancer susceptibility have been classified as XCIND (X-ray susceptibility, cancer, immunodeficiency, and neurologic defects), which also includes the aforementioned syndromes such as ataxia telangiectasia and Nijmegen breakage syndrome.
      • Hauck F.
      • Gennery A.R.
      • Seidel M.G.
      Editorial: The Relationship between cancer predisposition and primary immunodeficiency.
      • Hauck F.
      • Voss R.
      • Urban C.
      • Seidel M.G.
      Intrinsic and extrinsic causes of malignancies in patients with primary immunodeficiency disorders.
      • Mayor P.C.
      • Eng K.H.
      • Singel K.L.
      • et al.
      Cancer in primary immunodeficiency diseases: Cancer incidence in the United States Immune Deficiency Network Registry.
      • Derpoorter C.
      • Bordon V.
      • Laureys G.
      • Haerynck F.
      • Lammens T.
      Genes at the crossroad of primary immunodeficiencies and cancer.

      Clonal Plasma Cell Disorders/Dysproteinemias

      Similar to lymphoid neoplasms, familial clusters of monoclonal gammopathy of undetermined significance, MM, and Waldenstrom macroglobulinemia have been noted in population studies. In 2018, KDM1A/LSD1 was identified as the first inherited autosomal dominant gene, with an increased predisposition to develop MM. It encodes for a tumor-suppressor protein, which acts as an epigenetic transcriptional repressor by demethylating histone H3 on lysine 4 and regulates hematopoietic stem cell renewal.
      • Wei X.
      • Calvo-Vidal M.N.
      • Chen S.
      • et al.
      Germline lysine-specific demethylase 1 (LSD1/KDM1A) mutations confer susceptibility to multiple myeloma.
      Recently, exome sequencing has identified variants in the DIS3 gene in 2 families with MM.
      • Pertesi M.
      • Vallee M.
      • Wei X.
      • et al.
      Exome sequencing identifies germline variants in DIS3 in familial multiple myeloma.

      General Cancer Predisposition Syndromes

      Besides specific genomic variants associated with either myeloid, lymphoid, or plasma-cell neoplasms, established cancer predisposition syndromes, such as Li-Fraumeni, Lynch, and Down syndrome, also have increased predisposition toward developing hematopoietic neoplasms along with other cancers (Table 1). Approximately 70% of families of Li-Fraumeni syndrome harbor germline variants in the TP53 gene and develop early onset (age of onset ≤ 45 years) cancers such as soft tissue and osteosarcomas, adrenal cortical carcinoma, pancreatic, pediatric, and breast cancers, and leukemia, among others.
      • Li F.P.
      • Fraumeni Jr., J.F.
      • Mulvihill J.J.
      • et al.
      A cancer family syndrome in twenty-four kindreds.
      ,
      • Li F.P.
      • Fraumeni Jr., J.F.
      Soft-tissue sarcomas, breast cancer, and other neoplasms: a familial syndrome?.
      Lynch syndrome is genetically characterized by defects in the mismatch repair genes: namely, MSH1, MLH1, and MHS6.
      • Garber J.E.
      • Offit K.
      Hereditary cancer predisposition syndromes.
      Although hematopoietic malignancies are not traditionally included in the diagnostic criteria for this syndrome, leukemia (AML and CLL), MM and NHL have been associated predominantly with MSH2-related defect in mismatch repair.
      • Lynch H.T.
      • Snyder C.L.
      • Shaw T.G.
      • Heinen C.D.
      • Hitchins M.P.
      Milestones of Lynch syndrome: 1895-2015.
      ,
      • Bansidhar B.J.
      Extracolonic manifestations of lynch syndrome.
      Down syndrome is genomically characterized by the presence of trisomy 21 and truncating variants in the GATA1 gene, which predispose to the development of transient abnormal myelopoiesis, solid tumors such as retinoblastomas; testicular germ-cell tumors; lymphomas and leukemias, particularly acute megakaryocytic leukemia and B-cell ALL.
      • Mangaonkar A.A.
      • Patnaik M.M.
      Short telomere syndromes in clinical practice: bridging bench and bedside.
      Recently, an oncogenic hotspot gain-of-function variant in myeloid cytokine receptor gene, CSF2RB, was shown to cooperate with acquired variants in cohesion complex and epigenetic regulators and drive leukemic transformation from transient abnormal myelopoiesis in these patients.
      • Babushok D.V.
      • Stanley N.L.
      • Morrissette J.J.D.
      • et al.
      Germline duplication of ATG2B and GSKIP genes is not required for the familial myeloid malignancy syndrome associated with the duplication of chromosome 14q32.
      Detailed discussions of these syndromes are beyond the scope of this review and interested readers are referred to Garber et al.
      • Garber J.E.
      • Offit K.
      Hereditary cancer predisposition syndromes.
      Figure 1 provides a mechanistic overview of cellular functions disrupted by common HPS-associated germline variants.
      Figure thumbnail gr1
      Figure 1Figure showing cellular functions of putative pathogenic germline variants implicated in hereditary predisposition syndrome associated with hematopoietic neoplasms. Of note, only a few examples of involved genes are shown in the Figure. Please refer to the text for a comprehensive list of genes involved.

      Clinical Importance of HPS Identification

      Although precision genomics has improved the speed and accuracy of diagnosis for patients with HPS, its impact on therapy is also becoming increasingly relevant. As allogeneic HCT remains an integral part of management of bone marrow failure and malignancy in HPS, exclusion of variants in related sibling and/or haploidentical donors is critical to prevent post-HCT donor-derived malignancies.
      • Alter B.P.
      Inherited bone marrow failure syndromes: considerations pre- and posttransplant.
      Transplant-related morbidity and mortality is higher in patients with underlying HPS due to increased chemotherapy and radiation-therapy sensitivity, particularly pertinent for chromosomal breakage disorders and short telomere syndromes.
      • Pollard J.M.
      • Gatti R.A.
      Clinical radiation sensitivity with DNA repair disorders: an overview.
      • Uziel O.
      • Beery E.
      • Dronichev V.
      • et al.
      Telomere shortening sensitizes cancer cells to selected cytotoxic agents: in vitro and in vivo studies and putative mechanisms.
      • Mirjolet C.
      • Boidot R.
      • Saliques S.
      • Ghiringhelli F.
      • Maingon P.
      • Crehange G.
      The role of telomeres in predicting individual radiosensitivity of patients with cancer in the era of personalized radiotherapy.
      This leads to an excessive risk of cytopenias, infections, and complications from graft-versus-host disease. Further, owing to the underlying inherent bone marrow dysfunction, immune dysregulation, and use of less intensive conditioning regimens in HPS, patients are at a higher (~10-20%) risk for graft failure.
      • Lek M.
      • Karczewski K.J.
      • Minikel E.V.
      • et al.
      Analysis of protein-coding genetic variation in 60,706 humans.
      • Li Q.
      • Luo C.
      • Luo C.
      • et al.
      Disease-specific hematopoietic stem cell transplantation in children with inherited bone marrow failure syndromes.
      • Gadalla S.M.
      • Sales-Bonfim C.
      • Carreras J.
      • et al.
      Outcomes of allogeneic hematopoietic cell transplantation in patients with dyskeratosis congenita.
      Studies on alternate HCT-conditioning strategies (preferably without chemotherapy or radiation), appropriate donor selection (use of unrelated donors, exclusion of causative variant in related donors, alternate donor strategies such as cord blood) is necessary to pursue HCT safely in these patients.
      • Mangaonkar A.A.
      • Patnaik M.M.
      In Reply-Short telomere syndromes, biological aging, and hematopoietic stem cell transplantation.
      The benefit of genomic assessment is not limited to streamlining HCT management. At Mayo Clinic, our 2-year experience with a precision medicine clinic evaluating 68 patients with unexplained persistent (≥6 months) cytopenias (after exclusion of known infectious, autoimmune, toxic, and malignant causes; 29 [43%] with HPS) showed that genomic assessments resulted in an objective change in management in approximately 25% of tested patients.
      • Mangaonkar A.A.
      • Ferrer A.
      • Pinto E.V.F.
      • et al.
      Clinical applications and utility of a precision medicine approach for patients with unexplained cytopenias.
      Definition of a change in management included altered donor-selection strategy, conditioning regimen intensity, and/or initiation or discontinuation of a new drug and was chosen as per a similar study published by Alder et al., assessing utility of a clinical test to measure telomere length (flow cytometry-fluorescence in situ hybridization) in the hospital setting.
      • Alder J.K.
      • Hanumanthu V.S.
      • Strong M.A.
      • et al.
      Diagnostic utility of telomere length testing in a hospital-based setting.
      However, diagnosis can be challenging even for patients affected with syndromic HPS, as was recently shown by a recent Center for International Blood and Marrow Transplant Research (CIBMTR) study.
      • Myllymaki M.
      • Redd R.A.
      • Cutler C.S.
      • et al.
      Telomere length and telomerase complex mutations predict fatal treatment toxicity after stem cell transplantation in patients with myelodysplastic syndrome.
      Genomically defined HPS and related IBFMS have specific interventions that are necessary both from therapeutic and supportive-care standpoints. Specific examples include use of danazol in short telomere syndromes
      • Townsley D.M.
      • Dumitriu B.
      • Liu D.
      • et al.
      Danazol treatment for telomere diseases.
      (although controversial other reports have raised questions whether danazol truly prevents telomere attrition
      • Khincha P.P.
      • Bertuch A.A.
      • Gadalla S.M.
      • Giri N.
      • Alter B.P.
      • Savage S.A.
      Similar telomere attrition rates in androgen-treated and untreated patients with dyskeratosis congenita.
      ,
      • Khincha P.P.
      • Wentzensen I.M.
      • Giri N.
      • Alter B.P.
      • Savage S.A.
      Response to androgen therapy in patients with dyskeratosis congenita.
      ), azithromycin prophylaxis to prevent atypical mycobacterial infections in patients with GATA2 haploinsufficiency syndromes,
      • Spinner M.A.
      • Sanchez L.A.
      • Hsu A.P.
      • et al.
      GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity.
      use of granulocyte growth factor support for patients with severe congenital neutropenia,
      • Donini M.
      • Fontana S.
      • Savoldi G.
      • et al.
      G-CSF treatment of severe congenital neutropenia reverses neutropenia but does not correct the underlying functional deficiency of the neutrophil in defending against microorganisms.
      and upcoming investigational strategies such as post-transcriptional modulation of TERC by inhibition of PAPD5 in dyskeratosis congenita
      • Fok W.C.
      • Shukla S.
      • Vessoni A.T.
      • et al.
      Posttranscriptional modulation of TERC by PAPD5 inhibition rescues hematopoietic development in dyskeratosis congenita.
      and gene therapy,
      • Boztug K.
      • Schmidt M.
      • Schwarzer A.
      • et al.
      Stem-cell gene therapy for the Wiskott-Aldrich syndrome.
      among others.
      Finally, identification of HPS has important implications for screening family members. Owing to genetic phenomena such as incomplete penetrance and somatic reversion, relatives of affected individuals may carry the gene variant but may be clinically silent. Despite lack of early intervention strategies, it is important to offer them appropriate genetic counseling and testing.

      Our Approach to Diagnosis

      At Mayo Clinic, we follow a stepwise approach for identification of HPS. Clinical cues that suggest the need for screening include a younger age (≤40 years) at onset of cytopenias or diagnosis of a hematopoietic neoplasm; unexplained macrocytosis; elevated fetal hemoglobin; significant personal or family history of either a similar hematopoietic neoplasm, generalized cancer predisposition syndrome, or a bone marrow-failure syndrome associated with HPS; and syndromic features associated with unique genetic abnormalities (HPV-driven warts and warts, lymphedema, and monocytopenia for GATA2 haploinsufficiency, and reticulocytopenia for DBA [Table 2]). These patients are referred to precision medicine clinics where patients are evaluated by physicians, undergo genetic counseling, and get consented for research-based precision genomics testing. After history and physical examination, a detailed family history is obtained. A bone marrow evaluation (aspirate and biopsy) is performed, if clinically indicated. Based on the suspected clinical syndrome, specific clinical tests (for example, flow cytometry-fluorescence in situ hybridization to measure telomere length, chromosomal breakage assays for Fanconi anemia), and custom-designed targeted panel is ordered (Supplemental Table 1). If a pathogenic variant is discovered, germline confirmation is carried out with either testing in affected/unaffected family members or germline tissue. Germline tissue options include skin fibroblasts, hair follicles, nail clippings, CD3+ T-cells, and buccal swabs, each with their own disadvantages (Supplemental Table 2, available online at http://www.mayoclinicproceedings.org). Nail clippings often give a lower DNA yield, T cells may not be ideal germline controls for all HPS, and buccal swabs may be contaminated with leukocytes. One report also claimed skin biopsy to be unsatisfactory owing to a high number of false positive results.
      • Padron E.
      • Ball M.C.
      • Teer J.K.
      • et al.
      Germ line tissues for optimal detection of somatic variants in myelodysplastic syndromes.
      In our experience, skin fibroblasts offer reliable results and serve as our preferred germline control. If a variant of uncertain significance is found, a dedicated bioinformatics team assesses in silico predictions, sequence conservation through species, and presence or absence in various publicly available population databases. Cases are then discussed in a genomics tumor board, comprising clinicians, geneticists, bioinformaticians, and molecular biologists. Confirmation studies are then carried out after a consensus in a functional validation laboratory. If targeted panel testing results are negative, a research-based whole-exome sequencing data analysis is carried out, with a similar approach for pathogenic variants and variants of uncertain significance (Figure 2).
      Table 2Table Highlights Clinical Cues (Other Than Malignancies) That Can Alert Clinicians to Diagnose Patients With Specific Hereditary Predisposition Syndromes
      SyndromeClinical features
      General cuesYoung age of onset of cytopenias (age ≤ 40 years), persistent unexplained cytopenias (≥3 months), prolonged period of cytopenia before diagnosis of a hematopoietic malignancy, elevated fetal hemoglobin level, unexplained macrocytosis and/or hypocellularity on bone marrow evaluation, unexplained monocytopenia, reticulocytopenia or opportunistic infections, positive family history of a hereditary predisposition syndrome in one or more first- or second- degree relative
      Short telomere syndromesPremature greying of hair (age ≤ 30 years), oral leukoplakia, idiopathic pulmonary fibrosis, cryptogenic cirrhosis, unexplained cytopenias and/or immunodeficiency
      Fanconi anemiaShort stature, microcephaly, development delay, urogenital abnormalities, cutaneous warts, café-au-lait skin lesions
      GATA2 haploinsufficiencyLymphedema, monocytopenia, recurrent nontuberculous mycobacterial, fungal and viral infections, pulmonary alveolar proteinosis, anogenital warts
      Diamond-Blackfan anemiaEarly-onset macrocytic anemia, craniofacial, genitourinary and cardiac abnormalities, normocellular bone marrow with erythroid hypoplasia.
      Shwachman-Diamond syndromeSkeletal and neurodevelopmental abnormalities, exocrine pancreatic insufficiency
      Thrombocytopenia-absent radii syndromeThrombocytopenia, bilateral radius hypoplasia
      Severe congenital neutropeniaVaried phenotype and depends on genetic association. Common associations include immunodeficiency, skeletal defects, stunted growth, skin hypopigmentation, recurrent infections, neurological defects
      Figure thumbnail gr2
      Figure 2Figure showing a stepwise algorithmic approach toward identification and management of HPS at our institution. HPS = hereditary predisposition syndrome; VUS = variants of uncertain significance; WES = whole-exome sequencing.

      Future Directions

      Genomic characterization of HPS has expanded our knowledge on the biological underpinnings of these unique disorders. Studying the mechanism of clonal evolution and neoplastic transformation in these patients are expected to yield novel insights into treatment strategies aimed at altering their natural history. Investigations into how these genetically deficient cells survive and allow clonal selection/proliferation would guide drug development directed against specific therapeutic vulnerabilities. The advent of gene-editing technologies offers another therapeutic avenue.

      Conclusions

      Early recognition of hereditary predisposition to hematopoietic neoplasms is paramount to allow timely diagnosis and direct personalized management. A stepwise genomics approach enables an accurate diagnosis in a majority of patients and helps avoid contextually inadvertent treatments. Future areas of study include feasibility and applicability of such specialized multidisciplinary precision medicine clinics, innovative strategies for variant validation and transplant conditioning, and novel therapies to prevent clonal evolution and reverse genetic discrepancies in HPS.

      Supplemental Online Material

      References

        • Gunz F.
        • Dameshek W.
        Chronic lymphocytic leukemia in a family, including twin brothers and a son.
        JAMA. 1957; 164: 1323-1325
        • Fitzgerald P.H.
        • Crossen P.E.
        • Adams A.C.
        • Sharman C.V.
        • Gunz F.W.
        Chromosome studies in familial leukaemia.
        J Med Genet. 1966; 3: 96-100
        • Gunz F.W.
        • Gunz J.P.
        • Veale A.M.
        • Chapman C.J.
        • Houston I.B.
        Familial leukaemia: a study of 909 families.
        Scand J Hematol. 1975; 15: 117-131
        • Gunz F.W.
        • Gunz J.P.
        • Vincent P.C.
        • et al.
        Thirteen cases of leukemia in a family.
        J Natl Cancer Inst. 1978; 60: 1243-1250
        • Song W.J.
        • Sullivan M.G.
        • Legare R.D.
        • et al.
        Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia.
        Nat Genet. 1999; 23: 166-175
        • Smith M.L.
        • Cavenagh J.D.
        • Lister T.A.
        • Fitzgibbon J.
        Mutation of CEBPA in familial acute myeloid leukemia.
        N Engl J Med. 2004; 351: 2403-2407
        • Ostergaard P.
        • Simpson M.A.
        • Connell F.C.
        • et al.
        Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome).
        Nat Genet. 2011; 43: 929-931
        • Noris P.
        • Perrotta S.
        • Seri M.
        • et al.
        Mutations in ANKRD26 are responsible for a frequent form of inherited thrombocytopenia: analysis of 78 patients from 21 families.
        Blood. 2011; 117: 6673-6680
        • Pippucci T.
        • Savoia A.
        • Perrotta S.
        • et al.
        Mutations in the 5' UTR of ANKRD26, the ankirin repeat domain 26 gene, cause an autosomal-dominant form of inherited thrombocytopenia, THC2.
        Am J Hum Genet. 2011; 88: 115-120
        • Polprasert C.
        • Schulze I.
        • Sekeres M.A.
        • et al.
        Inherited and somatic defects in DDX41 in myeloid neoplasms.
        Cancer Cell. 2015; 27: 658-670
        • Zhang M.Y.
        • Churpek J.E.
        • Keel S.B.
        • et al.
        Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy.
        Nat Genet. 2015; 47: 180-185
        • Townsley D.M.
        • Dumitriu B.
        • Young N.S.
        Bone marrow failure and the telomeropathies.
        Blood. 2014; 124: 2775-2783
        • Kirwan M.
        • Beswick R.
        • Walne A.J.
        • et al.
        Dyskeratosis congenita and the DNA damage response.
        Br J Haematol. 2011; 153: 634-643
        • Levine A.J.
        • Momand J.
        • Finlay C.A.
        The p53 tumour suppressor gene.
        Nature. 1991; 351: 453-456
        • Arber D.A.
        • Orazi A.
        • Hasserjian R.
        • et al.
        The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.
        Blood. 2016; 127: 2391-2405
        • Wei X.
        • Calvo-Vidal M.N.
        • Chen S.
        • et al.
        Germline lysine-specific demethylase 1 (LSD1/KDM1A) mutations confer susceptibility to multiple myeloma.
        Cancer Res. 2018; 78: 2747-2759
        • Pertesi M.
        • Vallee M.
        • Wei X.
        • et al.
        Exome sequencing identifies germline variants in DIS3 in familial multiple myeloma.
        Leukemia. 2019; 33: 2324-2330
        • Patnaik M.M.
        • Lasho T.L.
        • Vijayvargiya P.
        • et al.
        Prognostic interaction between ASXL1 and TET2 mutations in chronic myelomonocytic leukemia.
        Blood Cancer J. 2016; 6: e385
        • Ho C.Y.
        • Otterud B.
        • Legare R.D.
        • et al.
        Linkage of a familial platelet disorder with a propensity to develop myeloid malignancies to human chromosome 21q22.1-22.2.
        Blood. 1996; 87: 5218-5224
        • Albers C.A.
        • Paul D.S.
        • Schulze H.
        • et al.
        Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome.
        Nat Genet. 2012; 44: 435-439
        • Tonelli R.
        • Scardovi A.L.
        • Pession A.
        • et al.
        Compound heterozygosity for two different amino-acid substitution mutations in the thrombopoietin receptor (c-mpl gene) in congenital amegakaryocytic thrombocytopenia (CAMT).
        Hum Genet. 2000; 107: 225-233
        • Kirwan M.
        • Walne A.J.
        • Plagnol V.
        • et al.
        Exome sequencing identifies autosomal-dominant SRP72 mutations associated with familial aplasia and myelodysplasia.
        Am J Hum Genet. 2012; 90: 888-892
        • Sanders M.A.
        • Chew E.
        • Flensburg C.
        • et al.
        MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML.
        Blood. 2018; 132: 1526-1534
        • Nagamachi A.
        • Matsui H.
        • Asou H.
        • et al.
        Haploinsufficiency of SAMD9L, an endosome fusion facilitator, causes myeloid malignancies in mice mimicking human diseases with monosomy 7.
        Cancer Cell. 2013; 24: 305-317
        • Narumi S.
        • Amano N.
        • Ishii T.
        • et al.
        SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7.
        Nat Genet. 2016; 48: 792-797
        • Schwartz J.R.
        • Wang S.
        • Ma J.
        • et al.
        Germline SAMD9 mutation in siblings with monosomy 7 and myelodysplastic syndrome.
        Leukemia. 2017; 31: 1827-1830
        • Maciaszek J.L.
        • Oak N.
        • Chen W.
        • et al.
        Enrichment of heterozygous germline RECQL4 loss-of-function variants in pediatric osteosarcoma.
        Cold Spring Harb Mol Case Stud. 2019; 5
        • Stieglitz E.
        • Loh M.L.
        Genetic predispositions to childhood leukemia.
        Ther Adv Hematol. 2013; 4: 270-290
        • Ghosh A.K.
        • Rossi M.L.
        • Singh D.K.
        • et al.
        RECQL4, the protein mutated in Rothmund-Thomson syndrome, functions in telomere maintenance.
        J Biol Chem. 2012; 287: 196-209
        • Tartaglia M.
        • Martinelli S.
        • Cazzaniga G.
        • et al.
        Genetic evidence for lineage-related and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia.
        Blood. 2004; 104: 307-313
        • Martinelli S.
        • Stellacci E.
        • Pannone L.
        • et al.
        Molecular diversity and associated Phenotypic spectrum of germline CBL mutations.
        Hum Mutat. 2015; 36: 787-796
        • Muraoka M.
        • Okuma C.
        • Kanamitsu K.
        • et al.
        Adults with germline CBL mutation complicated with juvenile myelomonocytic leukemia at infancy.
        J Hum Genet. 2016; 61: 523-526
        • Tapper W.
        • Jones A.V.
        • Kralovics R.
        • et al.
        Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms.
        Nat Comm. 2015; 6: 6691
        • Ballmaier M.
        • Germeshausen M.
        • Schulze H.
        • et al.
        c-mpl mutations are the cause of congenital amegakaryocytic thrombocytopenia.
        Blood. 2001; 97: 139-146
        • Boxer L.A.
        • Stein S.
        • Buckley D.
        • Bolyard A.A.
        • Dale D.C.
        Strong evidence for autosomal dominant inheritance of severe congenital neutropenia associated with ELA2 mutations.
        J Pediatr. 2006; 148: 633-636
        • Matsubara K.
        • Imai K.
        • Okada S.
        • et al.
        Severe developmental delay and epilepsy in a Japanese patient with severe congenital neutropenia due to HAX1 deficiency.
        Haematologica. 2007; 92: e123-e125
        • Touw I.P.
        Game of clones: the genomic evolution of severe congenital neutropenia.
        Hematology Am Soc Hematol Educ Program. 2015; 2015: 1-7
        • Beel K.
        • Vandenberghe P.
        G-CSF receptor (CSF3R) mutations in X-linked neutropenia evolving to acute myeloid leukemia or myelodysplasia.
        Haematologica. 2009; 94: 1449-1452
        • Oddsson A.
        • Kristinsson S.Y.
        • Helgason H.
        • et al.
        The germline sequence variant rs2736100_C in TERT associates with myeloproliferative neoplasms.
        Leukemia. 2014; 28: 1371-1374
        • Mangaonkar A.A.
        • Ferrer A.
        • Pinto E.V.F.
        • et al.
        Clinical correlates and treatment outcomes for patients with short telomere syndromes.
        Mayo Clin Proc. 2018; 93: 834-839
        • Mangaonkar A.A.
        • Patnaik M.M.
        Short telomere syndromes in clinical practice: bridging bench and bedside.
        Mayo Clin Proc. 2018; 93: 904-916
        • Shimamura A.
        • Alter B.P.
        Pathophysiology and management of inherited bone marrow failure syndromes.
        Blood Rev. 2010; 24: 101-122
        • Boocock G.R.
        • Morrison J.A.
        • Popovic M.
        • et al.
        Mutations in SBDS are associated with Shwachman-Diamond syndrome.
        Nat Genet. 2003; 33: 97-101
        • Dhanraj S.
        • Matveev A.
        • Li H.
        • et al.
        Biallelic mutations in DNAJC21 cause Shwachman-Diamond syndrome.
        Blood. 2017; 129: 1557-1562
        • D'Amours G.
        • Lopes F.
        • Gauthier J.
        • et al.
        Refining the phenotype associated with biallelic DNAJC21 mutations.
        Clin Genet. 2018; 94: 252-258
        • Stepensky P.
        • Chacon-Flores M.
        • Kim K.H.
        • et al.
        Mutations in EFL1, an SBDS partner, are associated with infantile pancytopenia, exocrine pancreatic insufficiency and skeletal anomalies in aShwachman-Diamond like syndrome.
        J Med Genet. 2017; 54: 558-566
        • Lipton J.M.
        • Ellis S.R.
        Diamond-Blackfan anemia: diagnosis, treatment, and molecular pathogenesis.
        Hematol Oncol Clin North Am. 2009; 23: 261-282
        • Ulirsch J.C.
        • Verboon J.M.
        • Kazerounian S.
        • et al.
        The genetic landscape of Diamond-Blackfan anemia.
        Am J Hum Genet. 2018; 103: 930-947
        • Vlachos A.
        • Rosenberg P.S.
        • Atsidaftos E.
        • Alter B.P.
        • Lipton J.M.
        Incidence of neoplasia in Diamond-Blackfan anemia: a report from the Diamond-Blackfan Anemia Registry.
        Blood. 2012; 119: 3815-3819
        • Sankaran V.G.
        • Ghazvinian R.
        • Do R.
        • et al.
        Exome sequencing identifies GATA1 mutations resulting in Diamond-Blackfan anemia.
        J Clin Invest. 2012; 122: 2439-2443
        • Ludwig L.S.
        • Gazda H.T.
        • Eng J.C.
        • et al.
        Altered translation of GATA1 in Diamond-Blackfan anemia.
        Nat Med. 2014; 20: 748-753
        • Klar J.
        • Khalfallah A.
        • Arzoo P.S.
        • Gazda H.T.
        • Dahl N.
        Recurrent GATA1 mutations in Diamond-Blackfan anaemia.
        Br J Haematol. 2014; 166: 949-951
        • Gripp K.W.
        • Curry C.
        • Olney A.H.
        • et al.
        Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28.
        Am J Med Genet A. 2014; 164a: 2240-2249
        • Saliba J.
        • Saint-Martin C.
        • Di Stefano A.
        • et al.
        Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies.
        Nat Genet. 2015; 47: 1131-1140
        • Babushok D.V.
        • Stanley N.L.
        • Morrissette J.J.D.
        • et al.
        Germline duplication of ATG2B and GSKIP genes is not required for the familial myeloid malignancy syndrome associated with the duplication of chromosome 14q32.
        Leukemia. 2018; 32: 2720-2723
        • Labuhn M.
        • Perkins K.
        • Matzk S.
        • et al.
        Mechanisms of progression of myeloid preleukemia to transformed myeloid leukemia in children with Down syndrome.
        Cancer Cell. 2019; 36: 123-138.e110
        • Churchman M.L.
        • Qian M.
        • Te Kronnie G.
        • et al.
        Germline genetic IKZF1 variation and predisposition to childhood acute lymphoblastic leukemia.
        Cancer Cell. 2018; 33: 937-948.e938
        • Shah S.
        • Schrader K.A.
        • Waanders E.
        • et al.
        A recurrent germline PAX5 mutation confers susceptibility to pre-B cell acute lymphoblastic leukemia.
        Nat Genet. 2013; 45: 1226-1231
        • Perez-Garcia A.
        • Ambesi-Impiombato A.
        • Hadler M.
        • et al.
        Genetic loss of SH2B3 in acute lymphoblastic leukemia.
        Blood. 2013; 122: 2425-2432
        • Coltro G.
        • Lasho T.L.
        • Finke C.M.
        • et al.
        Germline SH2B3 pathogenic variant associated with myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis.
        Am J Hematol. 2019; https://doi.org/10.1002/ajh.25552
        • Sarasin A.
        • Quentin S.
        • Droin N.
        • et al.
        Familial predisposition to TP53/complex karyotype MDS and leukemia in DNA repair-deficient xeroderma pigmentosum.
        Blood. 2019; 133: 2718-2724
        • Riaz I.B.
        • Faridi W.
        • Patnaik M.M.
        • Abraham R.S.
        A systematic review on predisposition to lymphoid (B and T cell) neoplasias in patients with primary immunodeficiencies and immune dysregulatory disorders (inborn errors of immunity).
        Front Immunol. 2019; 10: 777
        • Saarinen S.
        • Vahteristo P.
        • Launonen V.
        • et al.
        Analysis of KLHDC8B in familial nodular lymphocyte predominant Hodgkin lymphoma.
        Br J Haematol. 2011; 154: 413-415
        • Lynch H.T.
        • Snyder C.L.
        • Shaw T.G.
        • Heinen C.D.
        • Hitchins M.P.
        Milestones of Lynch syndrome: 1895-2015.
        Nat Rev Cancer. 2015; 15: 181-194
        • Pardanani A.
        • Fridley B.L.
        • Lasho T.L.
        • Gilliland D.G.
        • Tefferi A.
        Host genetic variation contributes to phenotypic diversity in myeloproliferative disorders.
        Blood. 2008; 111: 2785-2789
        • Pardanani A.
        • Lasho T.
        • McClure R.
        • Lacy M.
        • Tefferi A.
        Discordant distribution of JAK2V617F mutation in siblings with familial myeloproliferative disorders.
        Blood. 2006; 107: 4572-4573
        • Jones A.V.
        • Chase A.
        • Silver R.T.
        • et al.
        JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms.
        Nat Genet. 2009; 41: 446-449
        • Kilpivaara O.
        • Mukherjee S.
        • Schram A.M.
        • et al.
        A germline JAK2 SNP is associated with predisposition to the development of JAK2(V617F)-positive myeloproliferative neoplasms.
        Nat Genet. 2009; 41: 455-459
        • Hinds D.A.
        • Barnholt K.E.
        • Mesa R.A.
        • et al.
        Germ line variants predispose to both JAK2 V617F clonal hematopoiesis and myeloproliferative neoplasms.
        Blood. 2016; 128: 1121-1128
        • Harutyunyan A.S.
        • Giambruno R.
        • Krendl C.
        • et al.
        Germline RBBP6 mutations in familial myeloproliferative neoplasms.
        Blood. 2016; 127: 362-365
        • Rumi E.
        • Cazzola M.
        Advances in understanding the pathogenesis of familial myeloproliferative neoplasms.
        Br J Haematol. 2017; 178: 689-698
        • Germeshausen M.
        • Ancliff P.
        • Estrada J.
        • et al.
        MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia.
        Blood Adv. 2018; 2: 586-596
        • Vairo F.P.E.
        • Ferrer A.
        • Cathcart-Rake E.
        • et al.
        Novel germline missense DDX41 variant in a patient with an adult-onset myeloid neoplasm with excess blasts without dysplasia.
        Leuk Lymphoma. 2019; 60: 1337-1339
        • Douglas S.P.M.
        • Siipola P.
        • Kovanen P.E.
        • et al.
        ERCC6L2 defines a novel entity within inherited acute myeloid leukemia.
        Blood. 2019; 133: 2724-2728
        • Alter B.P.
        • Giri N.
        • Savage S.A.
        • Rosenberg P.S.
        Cancer in the National Cancer Institute inherited bone marrow failure syndrome cohort after fifteen years of follow-up.
        Haematologica. 2018; 103: 30-39
        • Quentin S.
        • Cuccuini W.
        • Ceccaldi R.
        • et al.
        Myelodysplasia and leukemia of Fanconi anemia are associated with a specific pattern of genomic abnormalities that includes cryptic RUNX1/AML1 lesions.
        Blood. 2011; 117: e161-170
        • Maung K.Z.Y.
        • Leo P.J.
        • Bassal M.
        • et al.
        Rare variants in Fanconi anemia genes are enriched in acute myeloid leukemia.
        Blood Cancer J. 2018; 8: 50
        • Armanios M.
        Telomerase mutations and the pulmonary fibrosis-bone marrow failure syndrome complex.
        N Engl J Med. 2012; 367 (author reply 384): 384
        • Armanios M.
        Telomerase and idiopathic pulmonary fibrosis.
        Mutat Res. 2012; 730: 52-58
        • Armanios M.
        • Blackburn E.H.
        The telomere syndromes.
        Nat Rev Genet. 2012; 13: 693-704
        • Marsh J.C.W.
        • Gutierrez-Rodrigues F.
        • Cooper J.
        • et al.
        Heterozygous RTEL1 variants in bone marrow failure and myeloid neoplasms.
        Blood Adv. 2018; 2: 36-48
        • Calvete O.
        • Garcia-Pavia P.
        • Dominguez F.
        • et al.
        The wide spectrum of POT1 gene variants correlates with multiple cancer types.
        Eur J Hum Genet. 2017; 25: 1278-1281
        • Speedy H.E.
        • Kinnersley B.
        • Chubb D.
        • et al.
        Germ line mutations in shelterin complex genes are associated with familial chronic lymphocytic leukemia.
        Blood. 2016; 128: 2319-2326
        • Stanley S.E.
        • Armanios M.
        The short and long telomere syndromes: paired paradigms for molecular medicine.
        Curr Opin Genet Dev. 2015; 33: 1-9
        • McNally E.J.
        • Luncsford P.J.
        • Armanios M.
        Long telomeres and cancer risk: the price of cellular immortality.
        J Clin Invest. 2019; 130: 3474-3481
        • Kazenwadel J.
        • Secker G.A.
        • Liu Y.J.
        • et al.
        Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature.
        Blood. 2012; 119: 1283-1291
        • Zhang S.J.
        • Ma L.Y.
        • Huang Q.H.
        • et al.
        Gain-of-function mutation of GATA-2 in acute myeloid transformation of chronic myeloid leukemia.
        Proc Natl Acad Sci U S A. 2008; 105: 2076-2081
        • Ganapathi K.A.
        • Townsley D.M.
        • Hsu A.P.
        • et al.
        GATA2 deficiency-associated bone marrow disorder differs from idiopathic aplastic anemia.
        Blood. 2015; 125: 56-70
        • Mir M.A.
        • Kochuparambil S.T.
        • Abraham R.S.
        • et al.
        Spectrum of myeloid neoplasms and immune deficiency associated with germline GATA2 mutations.
        Cancer Med. 2015; 4: 490-499
        • West R.R.
        • Hsu A.P.
        • Holland S.M.
        • Cuellar-Rodriguez J.
        • Hickstein D.D.
        Acquired ASXL1 mutations are common in patients with inherited GATA2 mutations and correlate with myeloid transformation.
        Haematologica. 2014; 99: 276-281
        • Dror Y.
        Shwachman-Diamond syndrome.
        Pediatric Blood Cancer. 2005; 45: 892-901
        • Valli R.
        • Minelli A.
        • Galbiati M.
        • et al.
        Shwachman-Diamond syndrome with clonal interstitial deletion of the long arm of chromosome 20 in bone marrow: haematological features, prognosis and genomic instability.
        Br J Haematol. 2019; 184: 974-981
        • Aziz A.
        • Baxter E.J.
        • Edwards C.
        • et al.
        Cooperativity of imprinted genes inactivated by acquired chromosome 20q deletions.
        J Clin Invest. 2013; 123: 2169-2182
        • Parrella S.
        • Aspesi A.
        • Quarello P.
        • et al.
        Loss of GATA-1 full length as a cause of Diamond-Blackfan anemia phenotype.
        Pediatric Blood Cancer. 2014; 61: 1319-1321
        • Zhou Q.
        • Yang D.
        • Ombrello A.K.
        • et al.
        Early-onset stroke and vasculopathy associated with mutations in ADA2.
        N Engl J Med. 2014; 370: 911-920
        • Dong F.
        • Brynes R.K.
        • Tidow N.
        • Welte K.
        • Lowenberg B.
        • Touw I.P.
        Mutations in the gene for the granulocyte colony-stimulating-factor receptor in patients with acute myeloid leukemia preceded by severe congenital neutropenia.
        N Engl J Med. 1995; 333: 487-493
        • Dong F.
        • Hoefsloot L.H.
        • Schelen A.M.
        • et al.
        Identification of a nonsense mutation in the granulocyte-colony-stimulating factor receptor in severe congenital neutropenia.
        Proc Natl Acad Sci U S A. 1994; 91: 4480-4484
        • Eash K.J.
        • Greenbaum A.M.
        • Gopalan P.K.
        • Link D.C.
        CXCR2 and CXCR4 antagonistically regulate neutrophil trafficking from murine bone marrow.
        J Clin Invest. 2010; 120: 2423-2431
        • Kawai T.
        • Choi U.
        • Cardwell L.
        • et al.
        WHIM syndrome myelokathexis reproduced in the NOD/SCID mouse xenotransplant model engrafted with healthy human stem cells transduced with C-terminus-truncated CXCR4.
        Blood. 2007; 109: 78-84
        • Person R.E.
        • Li F.Q.
        • Duan Z.
        • et al.
        Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2.
        Nat Genet. 2003; 34: 308-312
        • Abdollahpour H.
        • Appaswamy G.
        • Kotlarz D.
        • et al.
        The phenotype of human STK4 deficiency.
        Blood. 2012; 119: 3450-3457
        • McDermott D.H.
        • De Ravin S.S.
        • Jun H.S.
        • et al.
        Severe congenital neutropenia resulting from G6PC3 deficiency with increased neutrophil CXCR4 expression and myelokathexis.
        Blood. 2010; 116: 2793-2802
        • Bione S.
        • D'Adamo P.
        • Maestrini E.
        • Gedeon A.K.
        • Bolhuis P.A.
        • Toniolo D.
        A novel X-linked gene, G4.5. is responsible for Barth syndrome.
        Nat Genet. 1996; 12: 385-389
        • Huizing M.
        • Scher C.D.
        • Strovel E.
        • et al.
        Nonsense mutations in ADTB3A cause complete deficiency of the beta3A subunit of adaptor complex-3 and severe Hermansky-Pudlak syndrome type 2.
        Pediatr Res. 2002; 51: 150-158
        • Mostefai R.
        • Morice-Picard F.
        • Boralevi F.
        • et al.
        Poikiloderma with neutropenia, Clericuzio type, in a family from Morocco.
        Am J Med Genet A. 2008; 146a: 2762-2769
        • Gueneau L.
        • Duplomb L.
        • Sarda P.
        • et al.
        Congenital neutropenia with retinopathy, a new phenotype without intellectual deficiency or obesity secondary to VPS13B mutations.
        Am J Med Genet A. 2014; 164a: 522-527
        • Stepensky P.
        • Saada A.
        • Cowan M.
        • et al.
        The Thr224Asn mutation in the VPS45 gene is associated with the congenital neutropenia and primary myelofibrosis of infancy.
        Blood. 2013; 121: 5078-5087
        • Makaryan V.
        • Rosenthal E.A.
        • Bolyard A.A.
        • et al.
        TCIRG1-associated congenital neutropenia.
        Hum Mutat. 2014; 35: 824-827
        • Boztug K.
        • Jarvinen P.M.
        • Salzer E.
        • et al.
        JAGN1 deficiency causes aberrant myeloid cell homeostasis and congenital neutropenia.
        Nat Genet. 2014; 46: 1021-1027
        • Wortmann S.B.
        • Zietkiewicz S.
        • Kousi M.
        • et al.
        CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.
        Am J Hum Genet. 2015; 96: 245-257
        • Skokowa J.
        • Dale D.C.
        • Touw I.P.
        • Zeidler C.
        • Welte K.
        Severe congenital neutropenias.
        Nat Rev Dis Primers. 2017; 3: 17032
        • Ozbek M.N.
        • Senee V.
        • Aydemir S.
        • et al.
        Wolcott-Rallison syndrome due to the same mutation (W522X) in EIF2AK3 in two unrelated families and review of the literature.
        Pediatr Diabetes. 2010; 11: 279-285
        • Liewluck T.
        • Lovell T.L.
        • Bite A.V.
        • Engel A.G.
        Sporadic centronuclear myopathy with muscle pseudohypertrophy, neutropenia, and necklace fibers due to a DNM2 mutation.
        Neuromuscul Disord. 2010; 20: 801-804
        • Kawakami T.
        • He J.
        • Morita H.
        • et al.
        Rab27a is essential for the formation of neutrophil extracellular traps (NETs) in neutrophil-like differentiated HL60 cells.
        PLoS One. 2014; 9: e84704
        • Sorensen O.E.
        • Clemmensen S.N.
        • Dahl S.L.
        • et al.
        Papillon-Lefevre syndrome patient reveals species-dependent requirements for neutrophil defenses.
        J Clin Invest. 2014; 124: 4539-4548
        • Bohn G.
        • Allroth A.
        • Brandes G.
        • et al.
        A novel human primary immunodeficiency syndrome caused by deficiency of the endosomal adaptor protein p14.
        Nat Med. 2007; 13: 38-45
        • Menasche G.
        • Pastural E.
        • Feldmann J.
        • et al.
        Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome.
        Nat Genet. 2000; 25: 173-176
        • Rosenberg P.S.
        • Zeidler C.
        • Bolyard A.A.
        • et al.
        Stable long-term risk of leukaemia in patients with severe congenital neutropenia maintained on G-CSF therapy.
        Br J Haematol. 2010; 150: 196-199
        • Beekman R.
        • Touw I.P.
        G-CSF and its receptor in myeloid malignancy.
        Blood. 2010; 115: 5131-5136
        • Cerhan J.R.