Constitutional SAMD9L mutations cause familial myelodysplastic syndrome and transient monosomy 7
Victor B Pastor, Sushree S Sahoo, Jessica Boklan, Georg C Schwabe, Ebru Saribeyoglu, Brigitte Strahm, Dirk Lebrecht, Matthias Voss, Yenan T Bryceson, Miriam Erlacher, Gerhard Ehninger, Marena Niewisch, Brigitte Schlegelberger, Irith Baumann, John C Achermann, Akiko Shimamura, Jochen Hochrein, Ulf Tedgård, Lars Nilsson, Henrik Hasle, Melanie Boerries, Hauke Busch, Charlotte M Niemeyer, Marcin W Wlodarski, Victor B Pastor, Sushree S Sahoo, Jessica Boklan, Georg C Schwabe, Ebru Saribeyoglu, Brigitte Strahm, Dirk Lebrecht, Matthias Voss, Yenan T Bryceson, Miriam Erlacher, Gerhard Ehninger, Marena Niewisch, Brigitte Schlegelberger, Irith Baumann, John C Achermann, Akiko Shimamura, Jochen Hochrein, Ulf Tedgård, Lars Nilsson, Henrik Hasle, Melanie Boerries, Hauke Busch, Charlotte M Niemeyer, Marcin W Wlodarski
Abstract
Familial myelodysplastic syndromes arise from haploinsufficiency of genes involved in hematopoiesis and are primarily associated with early-onset disease. Here we describe a familial syndrome in seven patients from four unrelated pedigrees presenting with myelodysplastic syndrome and loss of chromosome 7/7q. Their median age at diagnosis was 2.1 years (range, 1-42). All patients presented with thrombocytopenia with or without additional cytopenias and a hypocellular marrow without an increase of blasts. Genomic studies identified constitutional mutations (p.H880Q, p.R986H, p.R986C and p.V1512M) in the SAMD9L gene on 7q21, with decreased allele frequency in hematopoiesis. The non-random loss of mutated SAMD9L alleles was attained via monosomy 7, deletion 7q, UPD7q, or acquired truncating SAMD9L variants p.R1188X and p.S1317RfsX21. Incomplete penetrance was noted in 30% (3/10) of mutation carriers. Long-term observation revealed divergent outcomes with either progression to leukemia and/or accumulation of driver mutations (n=2), persistent monosomy 7 (n=4), and transient monosomy 7 followed by spontaneous recovery with SAMD9L-wildtype UPD7q (n=2). Dysmorphic features or neurological symptoms were absent in our patients, pointing to the notion that myelodysplasia with monosomy 7 can be a sole manifestation of SAMD9L disease. Collectively, our results define a new subtype of familial myelodysplastic syndrome and provide an explanation for the phenomenon of transient monosomy 7. Registered at: www.clinicaltrials.gov; #NCT00047268.
Copyright© 2018 Ferrata Storti Foundation.
Figures
References
- Churpek JE, Godley LA. How I diagnose and manage individuals at risk for inherited myeloid malignancies. Blood. 2016;128(14):1800–1813.
- Feurstein S, Drazer MW, Godley LA. Genetic predisposition to leukemia and other hematologic malignancies. Semin Oncol. 2016;43(5):598–608.
- Hahn CN, Chong CE, Carmichael CL, et al. Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nat Genet. 2011;43(10):1012–1017.
- Smith ML, Cavenagh JD, Lister TA, Fitzgibbon J. Mutation of CEBPA in familial acute myeloid leukemia. N Engl J Med. 2004;351(23):2403–2407.
- Song WJ, Sullivan MG, Legare RD, et al. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat Genet. 1999;23(2):166–175.
- 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(1):115–120.
- Zhang MY, Churpek JE, Keel SB, et al. Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy. Nat Genet. 2015;47(2):180–185.
- Polprasert C, Schulze I, Sekeres MA, et al. Inherited and somatic defects in DDX41 in myeloid neoplasms. Cancer Cell. 2015;27(5):658–670.
- Wlodarski MW, Hirabayashi S, Pastor V, et al. Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents. Blood. 2016;127(11):1387–1397.
- Pastor V, Hirabayashi S, Karow A, et al. Mutational landscape in children with myelodysplastic syndromes is distinct from adults: specific somatic drivers and novel germline variants. Leukemia. 2017;31(3):759–762.
- Churpek JE, Pyrtel K, Kanchi KL, et al. Genomic analysis of germ line and somatic variants in familial myelodysplasia/acute myeloid leukemia. Blood. 2015;126(22):2484–2490.
- Gohring G, Michalova K, Beverloo HB, et al. Complex karyotype newly defined: the strongest prognostic factor in advanced childhood myelodysplastic syndrome. Blood. 2010;116(19):3766–3769.
- Kardos G, Baumann I, Passmore SJ, et al. Refractory anemia in childhood: a retrospective analysis of 67 patients with particular reference to monosomy 7. Blood. 2003;102(6):1997–2003.
- Mantadakis E, Shannon KM, Singer DA, et al. Transient monosomy 7 - A case series in children and review of the literature. Cancer. 1999;85(12):2655–2661.
- Parker TM, Klaassen RJ, Johnston DL. Spontaneous remission of myelodysplastic syndrome with monosomy 7 in a young boy. Cancer Genet Cytogenet. 2008;182(2):122–125.
- Leung EW, Woodman RC, Roland B, Abdelhaleem M, Freedman MH, Dror Y. Transient myelodysplastic syndrome associated with isochromosome 7q abnormality. Pediatr Hematol Oncol. 2003;20(7):539–545.
- Asou H, Matsui H, Ozaki Y, et al. Identification of a common microdeletion cluster in 7q21.3 subband among patients with myeloid leukemia and myelodysplastic syndrome. Biochem Biophys Res Commun. 2009;383(2):245–251.
- 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(3):305–317.
- Chen DH, Below JE, Shimamura A, et al. Ataxia-pancytopenia syndrome is caused by missense mutations in SAMD9L. Am J Hum Genet. 2016;98(6):1146–1158.
- Tesi B, Davidsson J, Voss M, et al. Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS and neurological symptoms. Blood. 2017;129(16):2266–2279.
- 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(7):792–797.
- Buonocore F, Kuhnen P, Suntharalingham JP, et al. Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans. J Clin Invest. 2017;127(5):1700–1713.
- Schwartz JR, Wang S, Ma J, et al. Germline SAMD9 mutation in siblings with monosomy 7 and myelodysplastic syndrome. Leukemia. 2017;31(8):1827–1830.
- Baumann I, Niemeyer CMBJ, Shannon K. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2008, 2008:104–107.
- Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classifi cation of the myeloid neoplasms. Blood. 2002;100(7):2292–2302.
- Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46(3):310–315.
- Grantham R. Amino acid difference formula to help explain protein evolution. Science. 1974;185(4154):862–864.
- Wlodarski MW, O’Keefe C, Howe EC, et al. Pathologic clonal cytotoxic T-cell responses: nonrandom nature of the T-cell-receptor restriction in large granular lymphocyte leukemia. Blood. 2005;106(8):2769–2780.
- Vraetz T, Emanuel PD, Niemeyer CM. In vitro regulation of colony stimulating factor-mediated hematopoiesis in healthy individuals and patients with different types of myeloproliferative disease. Methods Mol Biol. 2003;215:293–309.
- Lemos de Matos A, Liu J, McFadden G, Esteves PJ. Evolution and divergence of the mammalian SAMD9/SAMD9L gene family. BMC Evol Biol. 2013;13:121.
- Chefetz I, Ben Amitai D, Browning S, et al. Normophosphatemic familial tumoral calcinosis is caused by deleterious mutations in SAMD9, encoding a TNF-alpha responsive protein. J Invest Dermatol. 2008;128(6):1423–1429.
- Tanaka M, Shimbo T, Kikuchi Y, Matsuda M, Kaneda Y. Sterile alpha motif containing domain 9 is involved in death signaling of malignant glioma treated with inactivated Sendai virus particle (HVJ-E) or type I interferon. Int J Cancer. 2010;126(8):1982–1991.
- Hershkovitz D, Gross Y, Nahum S, et al. Functional characterization of SAMD9, a protein deficient in normophosphatemic familial tumoral calcinosis. J Invest Dermatol. 2011;131(3):662–669.
- Liu J, Wennier S, Zhang L, McFadden G. M062 is a host range factor essential for myxoma virus pathogenesis and functions as an antagonist of host SAMD9 in human cells. J Virol. 2011;85(7):3270–3282.
- Jongmans MCJ, Verwiel ETP, Heijdra Y, et al. Revertant somatic mosaicism by mitotic recombination in dyskeratosis congenita. Am J Hum Genet. 2012;90(3):426–433.
- Waisfisz Q, Morgan NV, Savino M, et al. Spontaneous functional correction of homozygous fanconi anaemia alleles reveals novel mechanistic basis for reverse mosaicism. Nat Genet. 1999;22(4):379–383.
- Reina-Castillon J, Pujol R, Lopez-Sanchez M, et al. Detectable clonal mosaicism in blood as a biomarker of cancer risk in Fanconi anemia. Blood Advances. 2017;1(5):319–329.
- Nagasawa M, Tomizawa D, Tsuji Y, et al. Pancytopenia presenting with monosomy 7 which disappeared after immunosuppressive therapy. Leuk Res. 2004;28(3):315–319.
- Benaim E, Hvizdala EV, Papenhausen P, Moscinski LC. Spontaneous remission in monosomy 7 myelodysplastic syndrome. Br J Haematol. 1995;89(4):947–948.
- Scheurlen W, Borkhardt A, Ritterbach J, Huppertz HI. Spontaneous hematological remission in a boy with myelodysplastic syndrome and monosomy 7. Leukemia. 1994;8(8):1435–1438.
Source: PubMed