Skip to main content
SpringerLink
Log in

Inherited/Genetic Predisposition to MDS and AML

  • Chapter
  • First Online:
Pathogenesis and Treatment of Leukemia

  • 458 Accesses

Abstract

Recognition of the importance of germline predisposition to hematopoietic malignancies, especially to the myeloid malignancies, is increasing with dramatic expansion in the number of involved genes. Diagnosis of germline predisposition has important implications for the clinical management of patients, choice of allogeneic stem cell donor, and surveillance strategies for patients and their relatives who share the deleterious variant. We now understand that there is extensive overlap in genes that confer risk for myeloid malignancies with those that confer risk for lymphoid malignancies, immunodeficiencies, and solid tumors, with more intersections likely to be uncovered in the future. Germline genetic testing should be considered standard of care now for anyone aged 40 or younger diagnosed with myelodysplastic syndrome given the high likelihood of identifying a deleterious variant. The increasing use of molecular profiling of malignant cells provides an opportunity to identify individuals without striking personal and/or family histories of cancer given how often predisposition genes are mutated somatically in these diseases and are therefore included on gene panels. The future will likely bring the identification of more risk genes, recognition of factors that promote leukemia development and development of diagnostic and surveillance guidelines for germline mutation carriers.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Galera P, Dulau-Florea A, Calvo KR. Inherited thrombocytopenia and platelet disorders with germline predisposition to myeloid neoplasia. Int J Lab Hematol. 2019;41(Suppl 1):131–41.

    PubMed  Google Scholar 

  2. Rafei H, DiNardo CD. Hereditary myeloid malignancies. Best Pract Res Clin Haematol. 2019;32(2):163–76.

    PubMed  PubMed Central  Google Scholar 

  3. Gocho Y, Yang JJ. Genetic defects in hematopoietic transcription factors and predisposition to acute lymphoblastic leukemia. Blood. 2019;134(10):793–7.

    PubMed  PubMed Central  Google Scholar 

  4. Weinberg OK, Kuo F, Calvo KR. Germline predisposition to hematolymphoid neoplasia. Am J Clin Pathol. 2019;152(3):258–76.

    PubMed  PubMed Central  Google Scholar 

  5. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–24.

    PubMed  PubMed Central  Google Scholar 

  6. Rivera-Munoz EA, Milko LV, Harrison SM, Azzariti DR, Kurtz CL, Lee K, et al. ClinGen Variant Curation Expert Panel experiences and standardized processes for disease and gene-level specification of the ACMG/AMP guidelines for sequence variant interpretation. Hum Mutat. 2018;39(11):1614–22.

    PubMed  PubMed Central  Google Scholar 

  7. Ma X, Does M, Raza A, Mayne ST. Myelodysplastic syndromes: incidence and survival in the United States. Cancer. 2007;109(8):1536–42.

    PubMed  Google Scholar 

  8. Rollison DE, Howlader N, Smith MT, Strom SS, Merritt WD, Ries LA, et al. Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001-2004, using data from the NAACCR and SEER programs. Blood. 2008;112(1):45–52.

    PubMed  Google Scholar 

  9. Strom SS, Velez-Bravo V, Estey EH. Epidemiology of myelodysplastic syndromes. Semin Hematol. 2008;45(1):8–13.

    PubMed  Google Scholar 

  10. Nagamachi A, Matsui H, Asou H, Ozaki Y, Aki D, Kanai A, et al. Haploinsufficiency of SAMD9L, an endosome fusion facilitator, causes myeloid malignancies in mice mimicking human diseases with monosomy 7. Cancer Cell. 2013;24(3):305–17.

    PubMed  Google Scholar 

  11. Chen DH, Below JE, Shimamura A, Keel SB, Matsushita M, Wolff J, et al. Ataxia-Pancytopenia Syndrome Is caused by missense mutations in SAMD9L. Am J Hum Genet. 2016;98(6):1146–58.

    PubMed  PubMed Central  Google Scholar 

  12. Narumi S, Amano N, Ishii T, Katsumata N, Muroya K, Adachi M, et al. SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7. Nat Genet. 2016;48(7):792–7.

    PubMed  Google Scholar 

  13. Wlodarski MW, Hirabayashi S, Pastor V, Stary J, Hasle H, Masetti R, et al. Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents. Blood. 2016;127(11):1387–97. quiz 518

    PubMed  Google Scholar 

  14. Sahoo SS, Kozyra EJ, Wlodarski MW. Germline predisposition in myeloid neoplasms: unique genetic and clinical features of GATA2 deficiency and SAMD9/SAMD9L syndromes. Best Pract Res Clin Haematol. 2020;33(3):101197.

    PubMed  PubMed Central  Google Scholar 

  15. Feurstein S, Churpek JE, Walsh T, Keel S, Hakkarainen M, Schroeder T, et al. Germline variants drive myelodysplastic syndrome in young adults. Leukemia epub. 2021;

    Google Scholar 

  16. Nagata Y, Narumi S, Guan Y, Przychodzen BP, Hirsch CM, Makishima H, et al. Germline loss-of-function SAMD9 and SAMD9L alterations in adult myelodysplastic syndromes. Blood. 2018;132(21):2309–13.

    PubMed  PubMed Central  Google Scholar 

  17. Davidsson J, Puschmann A, Tedgard U, Bryder D, Nilsson L, Cammenga J. SAMD9 and SAMD9L in inherited predisposition to ataxia, pancytopenia, and myeloid malignancies. Leukemia. 2018;32(5):1106–15.

    PubMed  PubMed Central  Google Scholar 

  18. Tesi B, Davidsson J, Voss M, Rahikkala E, Holmes TD, Chiang SCC, et al. Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms. Blood. 2017;129(16):2266–79.

    PubMed  PubMed Central  Google Scholar 

  19. McReynolds LJ, Calvo KR, Holland SM. Germline GATA2 mutation and bone marrow failure. Hematol Oncol Clin North Am. 2018;32(4):713–28.

    PubMed  PubMed Central  Google Scholar 

  20. McReynolds LJ, Yang Y, Yuen Wong H, Tang J, Zhang Y, Mulé MP, et al. MDS-associated mutations in germline GATA2 mutated patients with hematologic manifestations. Leuk Res. 2019;76:70–5.

    PubMed  Google Scholar 

  21. Bresnick EH, Jung MM, Katsumura KR. Human GATA2 mutations and hematologic disease: how many paths to pathogenesis? Blood Adv. 2020;4(18):4584–92.

    PubMed  PubMed Central  Google Scholar 

  22. Hsu AP, Johnson KD, Falcone EL, Sanalkumar R, Sanchez L, Hickstein DD, et al. GATA2 haploinsufficiency caused by mutations in a conserved intronic element leads to MonoMAC syndrome. Blood. 2013;121(19):3830–7. s1-7

    PubMed  PubMed Central  Google Scholar 

  23. Soukup AA, Zheng Y, Mehta C, Wu J, Liu P, Cao M, et al. Single-nucleotide human disease mutation inactivates a blood-regenerative GATA2 enhancer. J Clin Invest. 2019;129(3):1180–92.

    PubMed  PubMed Central  Google Scholar 

  24. Soukup AA, Bresnick EH. GATA2 +9.5 enhancer: from principles of hematopoiesis to genetic diagnosis in precision medicine. Curr Opin Hematol. 2020;27(3):163–71.

    PubMed  PubMed Central  Google Scholar 

  25. Wehr C, Grotius K, Casadei S, Bleckmann D, Bode SFN, Frye BC, et al. A novel disease-causing synonymous exonic mutation in GATA2 affecting RNA splicing. Blood. 2018;132(11):1211–5.

    PubMed  PubMed Central  Google Scholar 

  26. Fox LC, Tan M, Brown AL, Arts P, Thompson E, Ryland GL, et al. A synonymous GATA2 variant underlying familial myeloid malignancy with striking intrafamilial phenotypic variability. Br J Haematol. 2020;190(5):e297–301.

    PubMed  Google Scholar 

  27. Kozyra EJ, Pastor VB, Lefkopoulos S, Sahoo SS, Busch H, Voss RK, et al. Synonymous GATA2 mutations result in selective loss of mutated RNA and are common in patients with GATA2 deficiency. Leukemia. 2020;34(10):2673–87.

    PubMed  PubMed Central  Google Scholar 

  28. Cavalcante de Andrade Silva M, Katsumura KR, Mehta C, Velloso E, Bresnick EH, Godley LA. Breaking the spatial constraint between neighboring zinc fingers: a new germline mutation in GATA2 deficiency syndrome. Leukemia. 2021;35(1):264–8.

    PubMed  Google Scholar 

  29. Keel SB, Scott A, Sanchez-Bonilla M, Ho PA, Gulsuner S, Pritchard CC, et al. Genetic features of myelodysplastic syndrome and aplastic anemia in pediatric and young adult patients. Haematologica. 2016;101(11):1343–50.

    PubMed  PubMed Central  Google Scholar 

  30. Maciejewski JP, Padgett RA, Brown AL, Muller-Tidow C. DDX41-related myeloid neoplasia. Semin Hematol. 2017;54(2):94–7.

    PubMed  PubMed Central  Google Scholar 

  31. Cheah JJC, Hahn CN, Hiwase DK, Scott HS, Brown AL. Myeloid neoplasms with germline DDX41 mutation. Int J Hematol. 2017;106(2):163–74.

    PubMed  Google Scholar 

  32. Lewinsohn M, Brown AL, Weinel LM, Phung C, Rafidi G, Lee MK, et al. Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies. Blood. 2016;127(8):1017–23.

    PubMed  PubMed Central  Google Scholar 

  33. Quesada AE, Routbort MJ, DiNardo CD, Bueso-Ramos CE, Kanagal-Shamanna R, Khoury JD, et al. DDX41 mutations in myeloid neoplasms are associated with male gender, TP53 mutations and high-risk disease. Am J Hematol. 2019;94(7):757–66.

    PubMed  Google Scholar 

  34. Sebert M, Passet M, Raimbault A, Rahme R, Raffoux E, Sicre de Fontbrune F, et al. Germline DDX41 mutations define a significant entity within adult MDS/AML patients. Blood. 2019;134(17):1441–4.

    PubMed  Google Scholar 

  35. Schlegelberger B, Heller PG. RUNX1 deficiency (familial platelet disorder with predisposition to myeloid leukemia, FPDMM). Semin Hematol. 2017;54(2):75–80.

    PubMed  Google Scholar 

  36. Luo X, Feurstein S, Mohan S, Porter CC, Jackson SA, Keel S, et al. ClinGen Myeloid Malignancy Variant Curation Expert Panel recommendations for germline RUNX1 variants. Blood Adv. 2019;3(20):2962–79.

    PubMed  PubMed Central  Google Scholar 

  37. Wu D, Luo X, Feurstein S, Kesserwan C, Mohan S, Pineda-Alvarez DE, et al. How I curate: applying American Society of Hematology-Clinical Genome Resource Myeloid Malignancy Variant Curation Expert Panel rules for RUNX1 variant curation for germline predisposition to myeloid malignancies. Haematologica. 2020;105(4):870–87.

    PubMed  PubMed Central  Google Scholar 

  38. Song WJ, Sullivan MG, Legare RD, Hutchings S, Tan X, Kufrin D, et al. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat Genet. 1999;23(2):166–75.

    PubMed  Google Scholar 

  39. Yokota A, Huo L, Lan F, Wu J, Huang G. The clinical, molecular, and mechanistic basis of RUNX1 mutations identified in hematological malignancies. Mol Cells. 2020;43(2):145–52.

    PubMed  PubMed Central  Google Scholar 

  40. Churpek JE, Pyrtel K, Kanchi KL, Shao J, Koboldt D, Miller CA, et al. Genomic analysis of germ line and somatic variants in familial myelodysplasia/acute myeloid leukemia. Blood. 2015;126(22):2484–90.

    PubMed  PubMed Central  Google Scholar 

  41. Brown AL, Arts P, Carmichael CL, Babic M, Dobbins J, Chong CE, et al. RUNX1-mutated families show phenotype heterogeneity and a somatic mutation profile unique to germline predisposed AML. Blood Adv. 2020;4(6):1131–44.

    PubMed  PubMed Central  Google Scholar 

  42. Prebet T, Carbuccia N, Raslova H, Favier R, Rey J, Arnoulet C, et al. Concomitant germ-line RUNX1 and acquired ASXL1 mutations in a T-cell acute lymphoblastic leukemia. Eur J Haematol. 2013;91(3):277–9.

    PubMed  Google Scholar 

  43. Yoshimi A, Toya T, Kawazu M, Ueno T, Tsukamoto A, Iizuka H, et al. Recurrent CDC25C mutations drive malignant transformation in FPD/AML. Nat Commun. 2014;5:4770.

    PubMed  Google Scholar 

  44. Antony-Debre I, Duployez N, Bucci M, Geffroy S, Micol JB, Renneville A, et al. Somatic mutations associated with leukemic progression of familial platelet disorder with predisposition to acute myeloid leukemia. Leukemia. 2016;30(4):999–1002.

    PubMed  Google Scholar 

  45. Hamilton KV, Maese L, Marron JM, Pulsipher MA, Porter CC, Nichols KE. Stopping leukemia in Its tracks: Should preemptive hematopoietic stem-cell transplantation be offered to patients at increased genetic risk for acute myeloid leukemia? J Clin Oncol. 2019;37(24):2098–104.

    PubMed  Google Scholar 

  46. Bresnick EH, Johnson KD. Blood disease-causing and -suppressing transcriptional enhancers: general principles and GATA2 mechanisms. Blood Adv. 2019;3(13):2045–56.

    PubMed  PubMed Central  Google Scholar 

  47. Shimizu R, Yamamoto M. Quantitative and qualitative impairments in GATA2 and myeloid neoplasms. IUBMB Life. 2020;72(1):142–50.

    PubMed  Google Scholar 

  48. Spinner MA, Sanchez LA, Hsu AP, Shaw PA, Zerbe CS, Calvo KR, et al. GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. Blood. 2014;123(6):809–21.

    PubMed  PubMed Central  Google Scholar 

  49. Kallen ME, Dulau-Florea A, Wang W, Calvo KR. Acquired and germline predisposition to bone marrow failure: diagnostic features and clinical implications. Semin Hematol. 2019;56(1):69–82.

    PubMed  Google Scholar 

  50. McReynolds LJ, Zhang Y, Yang Y, Tang J, Mulé M, Hsu AP, et al. Rapid progression to AML in a patient with germline GATA2 mutation and acquired NRAS Q61K mutation. Leuk Res Rep. 2019;12:100176.

    PubMed  PubMed Central  Google Scholar 

  51. Parta M, Shah NN, Baird K, Rafei H, Calvo KR, Hughes T, et al. Allogeneic hematopoietic stem cell transplantation for GATA2 deficiency using a busulfan-based regimen. Biol Blood Marrow Transpl. 2018;24(6):1250–9.

    Google Scholar 

  52. Tawana K, Rio-Machin A, Preudhomme C, Fitzgibbon J. Familial CEBPA-mutated acute myeloid leukemia. Semin Hematol. 2017;54(2):87–93.

    PubMed  Google Scholar 

  53. Pathak A, Seipel K, Pemov A, Dewan R, Brown C, Ravichandran S, et al. Whole exome sequencing reveals a C-terminal germline variant in CEBPA-associated acute myeloid leukemia: 45-year follow up of a large family. Haematologica. 2016;101(7):846–52.

    PubMed  PubMed Central  Google Scholar 

  54. Tawana K, Wang J, Renneville A, Bodor C, Hills R, Loveday C, et al. Disease evolution and outcomes in familial AML with germline CEBPA mutations. Blood. 2015;126(10):1214–23.

    PubMed  Google Scholar 

  55. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–405.

    PubMed  Google Scholar 

  56. Peterson LC, Bloomfield CD, Niemeyer CM, Doehner H, Godley LA. Myeloid neoplasms with germline predisposition. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (Revised 4th edition). Lyon: IARC; 2017. pp. 121–128.

    Google Scholar 

  57. Greenberg PL, Stone RM, Al-Kali A, Barta SK, Bejar R, Bennett JM, et al. Myelodysplastic syndromes, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Cancer Netw. 2017;15(1):60–87.

    Google Scholar 

  58. Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424–47.

    PubMed  PubMed Central  Google Scholar 

  59. The University of Chicago Hematopoietic Malignancies Cancer Risk Team. How I diagnose and manage individuals at risk for inherited myeloid malignancies. Blood. 2016;128(14):1800–13.

    PubMed Central  Google Scholar 

  60. Kraft IL, Godley LA. Identifying potential germline variants from sequencing hematopoietic malignancies. Blood. 2020;136(22):2498–506.

    PubMed  Google Scholar 

  61. Tawana K, Drazer MW, Churpek JE. Universal genetic testing for inherited susceptibility in children and adults with myelodysplastic syndrome and acute myeloid leukemia: are we there yet? Leukemia. 2018;32(7):1482–92.

    PubMed  Google Scholar 

  62. Churpek JE, Artz A, Bishop M, Liu H, Godley LA. Correspondence regarding the consensus statement from the worldwide network for blood and marrow transplantation standing committee on donor issues. Biol Blood Marrow Transpl. 2016;22(1):183–4.

    Google Scholar 

  63. Hirschhorn R, Yang DR, Puck JM, Huie ML, Jiang CK, Kurlandsky LE. Spontaneous in vivo reversion to normal of an inherited mutation in a patient with adenosine deaminase deficiency. Nat Genet. 1996;13(3):290–5.

    PubMed  Google Scholar 

  64. Ariga T, Oda N, Yamaguchi K, Kawamura N, Kikuta H, Taniuchi S, et al. T-cell lines from 2 patients with adenosine deaminase (ADA) deficiency showed the restoration of ADA activity resulted from the reversion of an inherited mutation. Blood. 2001;97(9):2896–9.

    PubMed  Google Scholar 

  65. Ellis NA, Ciocci S, German J. Back mutation can produce phenotype reversion in Bloom syndrome somatic cells. Hum Genet. 2001;108(2):167–73.

    PubMed  Google Scholar 

  66. Weigelt B, Comino-Méndez I, de Bruijn I, Tian L, Meisel JL, García-Murillas I, et al. Diverse BRCA1 and BRCA2 reversion mutations in circulating cell-free DNA of therapy-resistant breast or ovarian cancer. Clin Cancer Res. 2017;23(21):6708–20.

    PubMed  PubMed Central  Google Scholar 

  67. Eoh KJ, Kim HM, Lee JY, Kim S, Kim SW, Kim YT, et al. Mutation landscape of germline and somatic BRCA1/2 in patients with high-grade serous ovarian cancer. BMC Cancer. 2020;20(1):204.

    PubMed  PubMed Central  Google Scholar 

  68. Vidula N, Rich TA, Sartor O, Yen J, Hardin A, Nance T, et al. Routine plasma-based genotyping to comprehensively detect germline, somatic, and reversion BRCA mutations among patients with advanced solid tumors. Clin Cancer Res. 2020;26(11):2546–55.

    PubMed  Google Scholar 

  69. Fuchs S, Rensing-Ehl A, Pannicke U, Lorenz MR, Fisch P, Jeelall Y, et al. Omenn syndrome associated with a functional reversion due to a somatic second-site mutation in CARD11 deficiency. Blood. 2015;126(14):1658–69.

    PubMed  PubMed Central  Google Scholar 

  70. Venugopal P, Moore S, Lawrence DM, George AJ, Hannan RD, Bray SC, et al. Self-reverting mutations partially correct the blood phenotype in a Diamond Blackfan anemia patient. Haematologica. 2017;102(12):e506–e9.

    PubMed  PubMed Central  Google Scholar 

  71. Jongmans MCJ, Diets IJ, Quarello P, Garelli E, Kuiper RP, Pfundt R. Somatic reversion events point towards RPL4 as a novel disease gene in a condition resembling Diamond-Blackfan anemia. Haematologica. 2018;103(12):e607–e9.

    PubMed  PubMed Central  Google Scholar 

  72. Garelli E, Quarello P, Giorgio E, Carando A, Menegatti E, Mancini C, et al. Spontaneous remission in a Diamond-Blackfan anaemia patient due to a revertant uniparental disomy ablating a de novo RPS19 mutation. Br J Haematol. 2019;185(5):994–8.

    PubMed  Google Scholar 

  73. Jing H, Zhang Q, Zhang Y, Hill BJ, Dove CG, Gelfand EW, et al. Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype. J Allergy Clin Immunol. 2014;133(6):1667–75.

    PubMed  PubMed Central  Google Scholar 

  74. Jongmans MC, Verwiel ET, Heijdra Y, Vulliamy T, Kamping EJ, Hehir-Kwa JY, et al. Revertant somatic mosaicism by mitotic recombination in dyskeratosis congenita. Am J Hum Genet. 2012;90(3):426–33.

    PubMed  PubMed Central  Google Scholar 

  75. Alder JK, Stanley SE, Wagner CL, Hamilton M, Hanumanthu VS, Armanios M. Exome sequencing identifies mutant TINF2 in a family with pulmonary fibrosis. Chest. 2015;147(5):1361–8.

    PubMed  Google Scholar 

  76. Lo Ten Foe JR, Kwee ML, Rooimans MA, Oostra AB, Veerman AJ, van Weel M, et al. Somatic mosaicism in Fanconi anemia: molecular basis and clinical significance. Eur J Hum Genet. 1997;5(3):137–48.

    PubMed  Google Scholar 

  77. Waisfisz Q, Morgan NV, Savino M, de Winter JP, van Berkel CG, Hoatlin ME, et al. Spontaneous functional correction of homozygous Fanconi Anaemia alleles reveals novel mechanistic basis for reverse mosaicism. Nat Genet. 1999;22(4):379–83.

    PubMed  Google Scholar 

  78. Gross M, Hanenberg H, Lobitz S, Friedl R, Herterich S, Dietrich R, et al. Reverse mosaicism in Fanconi anemia: natural gene therapy via molecular self-correction. Cytogenet Genome Res. 2002;98(2–3):126–35.

    PubMed  Google Scholar 

  79. Soulier J, Leblanc T, Larghero J, Dastot H, Shimamura A, Guardiola P, et al. Detection of somatic mosaicism and classification of Fanconi anemia patients by analysis of the FA/BRCA pathway. Blood. 2005;105(3):1329–36.

    PubMed  Google Scholar 

  80. Stephan V, Wahn V, Le Deist F, Dirksen U, Broker B, Müller-Fleckenstein I, et al. Atypical X-linked severe combined immunodeficiency due to possible spontaneous reversion of the genetic defect in T cells. N Engl J Med. 1996;335(21):1563–7.

    PubMed  Google Scholar 

  81. Buonocore F, Kühnen P, Suntharalingham JP, Del Valle I, Digweed M, Stachelscheid H, et al. Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans. J Clin Invest. 2017;127(5):1700–13.

    PubMed  PubMed Central  Google Scholar 

  82. Shima H, Koehler K, Nomura Y, Sugimoto K, Satoh A, Ogata T, et al. Two patients with MIRAGE syndrome lacking haematological features: role of somatic second-site reversion SAMD9 mutations. J Med Genet. 2018;55(2):81–5.

    PubMed  Google Scholar 

  83. Ariga T, Yamada M, Sakiyama Y, Tatsuzawa O. A case of Wiskott-Aldrich syndrome with dual mutations in exon 10 of the WASP gene: an additional de novo one-base insertion, which restores frame shift due to an inherent one-base deletion, detected in the major population of the patient's peripheral blood lymphocytes. Blood. 1998;92(2):699–701.

    PubMed  Google Scholar 

  84. Ariga T, Kondoh T, Yamaguchi K, Yamada M, Sasaki S, Nelson DL, et al. Spontaneous in vivo reversion of an inherited mutation in the Wiskott-Aldrich syndrome. J Immunol. 2001;166(8):5245–9.

    PubMed  Google Scholar 

  85. Wada T, Schurman SH, Otsu M, Garabedian EK, Ochs HD, Nelson DL, et al. Somatic mosaicism in Wiskott--Aldrich syndrome suggests in vivo reversion by a DNA slippage mechanism. Proc Natl Acad Sci U S A. 2001;98(15):8697–702.

    PubMed  PubMed Central  Google Scholar 

  86. Padron E, Ball MC, Teer JK, Painter JS, Yoder SJ, Zhang C, et al. Germ line tissues for optimal detection of somatic variants in myelodysplastic syndromes. Blood. 2018;131(21):2402–5.

    PubMed  PubMed Central  Google Scholar 

  87. Roloff GW, Godley LA, Drazer MW. Assessment of technical heterogeneity among diagnostic tests to detect germline risk variants for hematopoietic malignancies. Genet Med. 2021;23(1):211–4.

    PubMed  Google Scholar 

  88. Polprasert C, Schulze I, Sekeres MA, Makishima H, Przychodzen B, Hosono N, et al. Inherited and somatic defects in DDX41 in myeloid neoplasms. Cancer Cell. 2015;27(5):658–70.

    PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Section of Hematology/Oncology, Department of Medicine, The University of Chicago Comprehensive Cancer Center, The University of Chicago, Chicago, IL, USA

    Lucy A. Godley

  2. Section of Hematology/Oncology, Department of Human Genetics, The University of Chicago Comprehensive Cancer Center, The University of Chicago, Chicago, IL, USA

    Lucy A. Godley

Authors
  1. Lucy A. Godley
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lucy A. Godley .

Editor information

Editors and Affiliations

  1. Department of Medicine, Queen Mary Hospital, Hongkong, Hong Kong

    Harinder Gill

  2. Department of Medicine, Queen Mary Hospital, Hongkong, Hong Kong

    Yok-Lam Kwong

Rights and permissions

Reprints and permissions

Copyright information

© 2023 The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Godley, L.A. (2023). Inherited/Genetic Predisposition to MDS and AML. In: Gill, H., Kwong, YL. (eds) Pathogenesis and Treatment of Leukemia. Springer, Singapore. https://doi.org/10.1007/978-981-99-3810-0_27

Download citation

  • DOI: https://doi.org/10.1007/978-981-99-3810-0_27

  • Published:

  • Publisher Name: Springer, Singapore

  • Print ISBN: 978-981-99-3809-4

  • Online ISBN: 978-981-99-3810-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation