Germline SAMD9 and SAMD9L mutations (SAMD9/9Lmut) predispose to myelodysplastic syndromes (MDS) with propensity for somatic rescue. In this study, we investigated a clinically annotated pediatric MDS cohort (n = 669) to define the prevalence, genetic landscape, phenotype, therapy outcome and clonal architecture of SAMD9/9L syndromes. In consecutively diagnosed MDS, germline SAMD9/9Lmut accounted for 8% and were mutually exclusive with GATA2 mutations present in 7% of the cohort. Among SAMD9/9Lmut cases, refractory cytopenia was the most prevalent MDS subtype (90%); acquired monosomy 7 was present in 38%; constitutional abnormalities were noted in 57%; and immune dysfunction was present in 28%. The clinical outcome was independent of germline mutations. In total, 67 patients had 58 distinct germline SAMD9/9Lmut clustering to protein middle regions. Despite inconclusive in silico prediction, 94% of SAMD9/9Lmut suppressed HEK293 cell growth, and mutations expressed in CD34+ cells induced overt cell death. Furthermore, we found that 61% of SAMD9/9Lmut patients underwent somatic genetic rescue (SGR) resulting in clonal hematopoiesis, of which 95% was maladaptive (monosomy 7 ± cancer mutations), and 51% had adaptive nature (revertant UPD7q, somatic SAMD9/9Lmut). Finally, bone marrow single-cell DNA sequencing revealed multiple competing SGR events in individual patients. Our findings demonstrate that SGR is common in SAMD9/9Lmut MDS and exemplify the exceptional plasticity of hematopoiesis in children.

Department of Haematology and Transfusiology National Institute of Children's Diseases Faculty of Medicine Comenius University Bratislava Slovakia

Department of Hematology and Oncology Hospital Sant Joan de Deu Barcelona Spain

Department of Hematology and Oncology University Children's Hospital Zurich Switzerland

Department of Hematology Oncology and General Pediatrics Children's University Hospital University of Tübingen Tübingen Germany

Department of Hematology St Jude Children's Research Hospital Memphis TN USA

Department of Human Genetics Hannover Medical School Hannover Germany

Department of Medicine 1 Medical Center University of Freiburg Faculty of Medicine University of Freiburg Freiburg Germany

Department of Paediatric Bone Marrow Transplantation Oncology and Hematology Wroclaw Medical University Wroclaw Poland

Department of Paediatric Haematology and Oncology 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Paediatric Haematology Oncology Ghent University Hospital Ghent Ghent Belgium

Department of Pediatric Haematology Oncology Children's Health Ireland at Crumlin Dublin Ireland

Department of Pediatric Hematology and Oncology Hannover Medical School Hannover Germany

Department of Pediatric Hematology and Oncology IRCCS Ospedale Pediatrico Bambino Gesù Sapienza University of Rome Rome Italy

Department of Pediatric Hematology and Oncology Oslo University Hospital Oslo Norway

Department of Pediatric Hematology and Stem Cell Transplantation Central Hospital of Southern Pest National Institute of Hematology and Infectious Diseases Budapest Hungary

Department of Pediatric Hematology Oncology Aghia Sophia Children's Hospital Athens Greece

Department of Pediatric Oncology Hematology and Clinical Immunology Division of Pediatric Stem Cell Therapy Medical Faculty Heinrich Heine University Duesseldorf Germany

Department of Pediatric Oncology Hematology Skåne University Hospital Lund Sweden

Department of Pediatrics Aarhus University Hospital Aarhus Denmark

Department of Pediatrics and Adolescent Medicine Division of Pediatric Hematology and Oncology Medical Center Faculty of Medicine University of Freiburg Freiburg Germany

Department of Pediatrics Dr von Hauner Children´s Hospital University Hospital LMU Munich Munich Germany

Department of Pediatrics St Anna Children's Hospital and Children's Cancer Research Institute Medical University of Vienna Vienna Austria

Department of Pediatrics University Hospital Schleswig Holstein Campus Kiel Kiel Germany

Department of Pediatrics University Medical Center Ulm Ulm Germany

Division for Stem Cell Transplantation and Immunology Department for Children and Adolescents University Hospital Frankfurt Frankfurt am Main Germany

Division of Hematology Oncology and SCT Children's Hospital University of Helsinki and Helsinki University Hospital Hus Finland

Division of Pediatric Hematology and Oncology Clinic of Pedatric Hematology and Oncology University Medical Center of Hamburg Eppendorf Hamburg Germany

Dutch Childhood Oncology Group Princess Máxima Center for Pediatric Oncology Utrecht Netherlands

Faculty of Biology University of Freiburg Freiburg Germany

German Cancer Consortium Heidelberg and Freiburg Germany

Institute of Digitalization in Medicine Faculty of Medicine University of Freiburg Freiburg Germany

Institute of Pathology Klinikum Kaufbeuren Ravensburg Kaufbeuren Germany

Institute of Pathology University Hospital Erlangen Erlangen Germany

Mission Bio Inc South San Francisco CA USA

Paediatric Oncology and Haematology IRCCS Azienda Ospedaliero Universitaria di Bologna Bologna Italy

Pediatric Hematology and Oncology University Hospital Muenster Muenster Germany

Pediatric Hematology Oncology Schneider Children's Medical Center of Israel Petah Tikva and Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel

University Hospital Essen Pediatric Haematology and Oncology Essen Germany

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Nat Med. 2021 Dec;27(12):2248. doi: 10.1038/s41591-021-01632-y. PubMed

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J Clin Immunol. 2024 Jan 17;44(2):43. doi: 10.1007/s10875-023-01650-0. PubMed

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Lemos de Matos A, Liu J, McFadden G & Esteves PJ Evolution and divergence of the mammalian SAMD9/SAMD9L gene family. BMC Evol Biol 13, 121 (2013). PubMed PMC

Wu L, et al. miR-96 induces cisplatin chemoresistance in non-small cell lung cancer cells by downregulating SAMD9. Oncol Lett 11, 945–952 (2016). PubMed PMC

Topaz O, et al. A deleterious mutation in SAMD9 causes normophosphatemic familial tumoral calcinosis. Am J Hum Genet 79, 759–764 (2006). PubMed PMC

Liu J & McFadden G SAMD9 is an innate antiviral host factor with stress response properties that can be antagonized by poxviruses. J Virol 89, 1925–1931 (2015). PubMed PMC

Nagamachi A, et al. Haploinsufficiency of SAMD9L, an endosome fusion facilitator, causes myeloid malignancies in mice mimicking human diseases with monosomy 7. Cancer Cell 24, 305–317 (2013). PubMed

Narumi S, et al. SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7. Nat Genet 48, 792–797 (2016). PubMed

Thomas ME 3rd, et al. Pediatric MDS and bone marrow failure-associated germline mutations in SAMD9 and SAMD9L impair multiple pathways in primary hematopoietic cells. Leukemia (2021). PubMed PMC

Allenspach EJ, et al. Germline SAMD9L truncation variants trigger global translational repression. J Exp Med 218(2021). PubMed PMC

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. Journal of virology 85, 3270–3282 (2011). PubMed PMC

Meng X, Krumm B, Li Y, Deng J & Xiang Y Structural basis for antagonizing a host restriction factor by C7 family of poxvirus host-range proteins. Proc Natl Acad Sci U S A 112, 14858–14863 (2015). PubMed PMC

Nounamo B, et al. An interaction domain in human SAMD9 is essential for myxoma virus host-range determinant M062 antagonism of host anti-viral function. Virology 503, 94–102 (2017). PubMed PMC

Meng X, et al. A paralogous pair of mammalian host restriction factors form a critical host barrier against poxvirus infection. PLoS Pathog 14, e1006884 (2018). PubMed PMC

Mekhedov SL, Makarova KS & Koonin EV The complex domain architecture of SAMD9 family proteins, predicted STAND-like NTPases, suggests new links to inflammation and apoptosis. Biol Direct 12, 13 (2017). PubMed PMC

Jiang Q, et al. The Samd9L gene: transcriptional regulation and tissue-specific expression in mouse development. J Invest Dermatol 131, 1428–1434 (2011). PubMed PMC

Li CF, et al. Human sterile alpha motif domain 9, a novel gene identified as down-regulated in aggressive fibromatosis, is absent in the mouse. BMC Genomics 8, 92 (2007). PubMed PMC

Chen DH, et al. Ataxia-Pancytopenia Syndrome Is Caused by Missense Mutations in SAMD9L. Am J Hum Genet 98, 1146–1158 (2016). PubMed PMC

Tesi B, et al. Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS and neurological symptoms. Blood (2017). PubMed PMC

Schwartz JR, et al. Germline SAMD9 mutation in siblings with monosomy 7 and myelodysplastic syndrome. Leukemia 31, 1827–1830 (2017). PubMed PMC

Amano N, et al. Genetic defects in pediatric-onset adrenal insufficiency in Japan. Eur J Endocrinol 177, 187–194 (2017). PubMed

Jeffries L, et al. A novel SAMD9 mutation causing MIRAGE syndrome: An expansion and review of phenotype, dysmorphology, and natural history. Am J Med Genet A 176, 415–420 (2018). PubMed

Kim YM, et al. A case of an infant suspected as IMAGE syndrome who were finally diagnosed with MIRAGE syndrome by targeted Mendelian exome sequencing. BMC Med Genet 19, 35 (2018). PubMed PMC

Shima H, et al. Two patients with MIRAGE syndrome lacking haematological features: role of somatic second-site reversion SAMD9 mutations. J Med Genet 55, 81–85 (2018). PubMed

Shima H, et al. MIRAGE syndrome is a rare cause of 46,XY DSD born SGA without adrenal insufficiency. PLoS One 13, e0206184 (2018). PubMed PMC

Csillag B, et al. Somatic mosaic monosomy 7 and UPD7q in a child with MIRAGE syndrome caused by a novel SAMD9 mutation. Pediatr Blood Cancer 66, e27589 (2019). PubMed

Thunstrom S & Axelsson M Leukoencephalopathia, demyelinating peripheral neuropathy and dural ectasia explained by a not formerly described de novo mutation in the SAMD9L gene, ends 27 years of investigations - a case report. BMC Neurol 19, 89 (2019). PubMed PMC

Cheah JJC, et al. A novel germline SAMD9L mutation in a family with ataxia-pancytopenia syndrome and pediatric acute lymphoblastic leukemia. Haematologica 104, e318–e321 (2019). PubMed PMC

Mengen E & Kucukcongar Yavas A A Rare Etiology of 46, XY Disorder of Sex Development and Adrenal Insufficiency: A case of MIRAGE syndrome caused by mutations in SAMD9 gene. J Clin Res Pediatr Endocrinol (2019). PubMed PMC

Perisa MP, et al. A novel SAMD9 variant identified in patient with MIRAGE syndrome: Further defining syndromic phenotype and review of previous cases. Pediatr Blood Cancer 66, e27726 (2019). PubMed

Buonocore F, et al. Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans. J Clin Invest (2017). PubMed PMC

Schwartz JR, et al. The genomic landscape of pediatric myelodysplastic syndromes. Nat Commun 8, 1557 (2017). PubMed PMC

Wong JC, et al. Germline SAMD9 and SAMD9L mutations are associated with extensive genetic evolution and diverse hematologic outcomes. JCI Insight 3(2018). PubMed PMC

Bluteau O, et al. A landscape of germ line mutations in a cohort of inherited bone marrow failure patients. Blood 131, 717–732 (2018). PubMed

Pastor VB, et al. Constitutional SAMD9L mutations cause familial myelodysplastic syndrome and transient monosomy 7. Haematologica 103, 427–437 (2018). PubMed PMC

de Jesus AA, et al. Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases. J Clin Invest (2020). PubMed PMC

Ishiwa S, et al. A girl with MIRAGE syndrome who developed steroid-resistant nephrotic syndrome: a case report. BMC Nephrol 21, 340 (2020). PubMed PMC

Ahmed IA, et al. Outcomes of Hematopoietic Cell Transplantation in Patients with Germline SAMD9/SAMD9L Mutations. Biol Blood Marrow Transplant 25, 2186–2196 (2019). PubMed PMC

Yoshida M, et al. Prevalence of germline GATA2 and SAMD9/9L variants in paediatric haematological disorders with monosomy 7. Br J Haematol (2020). PubMed

Bamshad MJ, et al. Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet 12, 745–755 (2011). PubMed

Wlodarski MW, Collin M & Horwitz MS GATA2 deficiency and related myeloid neoplasms. Semin Hematol 54, 81–86 (2017). PubMed PMC

Revy P, Kannengiesser C & Fischer A Somatic genetic rescue in Mendelian haematopoietic diseases. Nat Rev Genet 20, 582–598 (2019). PubMed

Huisman SA, Redeker EJ, Maas SM, Mannens MM & Hennekam RC High rate of mosaicism in individuals with Cornelia de Lange syndrome. J Med Genet 50, 339–344 (2013). PubMed

Erickson RP Somatic gene mutation and human disease other than cancer: an update. Mutat Res 705, 96–106 (2010). PubMed

Jordan DM, et al. Identification of cis-suppression of human disease mutations by comparative genomics. Nature 524, 225–229 (2015). PubMed PMC

Leipe DD, Koonin EV & Aravind L STAND, a class of P-loop NTPases including animal and plant regulators of programmed cell death: multiple, complex domain architectures, unusual phyletic patterns, and evolution by horizontal gene transfer. J Mol Biol 343, 1–28 (2004). PubMed

Cordero MD, Alcocer-Gomez E & Ryffel B Gain of function mutation and inflammasome driven diseases in human and mouse models. J Autoimmun 91, 13–22 (2018). PubMed

Nagamachi A, et al. Multiorgan failure with abnormal receptor metabolism in mice mimicking Samd9/9L syndromes. J Clin Invest 131(2021). PubMed PMC

Sarthy J, et al. Poor outcome with hematopoietic stem cell transplantation for bone marrow failure and MDS with severe MIRAGE syndrome phenotype. Blood Adv 2, 120–125 (2018). PubMed PMC

Baumann I, Niemeyer CM, Bennett JM. Childhood myelodysplastic syndrome, in: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. in The 2016 Revision to the World Health Organization Classificatio of Myelodysplastic Syndromes (ed. al., S.S.e.) (International Agency for Research on Cancer, Lyon: 2017).

Tesi B, et al. Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS and neurological symptoms. Blood (2017). PubMed PMC

Bluteau O, et al. A landscape of germ line mutations in a cohort of inherited bone marrow failure patients. Blood 131, 717–732 (2018). PubMed

Pastor VB, et al. Constitutional SAMD9L mutations cause familial myelodysplastic syndrome and transient monosomy 7. Haematologica 103, 427–437 (2018). PubMed PMC

Richards S, 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 17, 405–424 (2015). PubMed PMC

Bailey MH, et al. Comprehensive Characterization of Cancer Driver Genes and Mutations. Cell 173, 371–385 e318 (2018). PubMed PMC

Ma X, et al. Pan-cancer genome and transcriptome analyses of 1,699 paediatric leukaemias and solid tumours. Nature 555, 371–376 (2018). PubMed PMC

Grobner SN, et al. The landscape of genomic alterations across childhood cancers. Nature 555, 321–327 (2018). PubMed

Zhang MY, et al. Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy. Nat Genet 47, 180–185 (2015). PubMed PMC

Lindsley RC, et al. Prognostic Mutations in Myelodysplastic Syndrome after Stem-Cell Transplantation. N Engl J Med 376, 536–547 (2017). PubMed PMC

Papaemmanuil E, et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood 122, 3616–3627; quiz 3699 (2013). PubMed PMC

Pastor V, et al. Mutational landscape in children with myelodysplastic syndromes is distinct from adults: specific somatic drivers and novel germline variants. Leukemia 31, 759–762 (2017). PubMed

Wang K, Li M & Hakonarson H ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38, e164 (2010). PubMed PMC

Ioannidis NM, et al. REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants. Am J Hum Genet 99, 877–885 (2016). PubMed PMC

Nykamp K, et al. Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Genet Med 19, 1105–1117 (2017). PubMed PMC

Shihab HA, et al. An integrative approach to predicting the functional effects of non-coding and coding sequence variation. Bioinformatics 31, 1536–1543 (2015). PubMed PMC

Mather CA, et al. CADD score has limited clinical validity for the identification of pathogenic variants in noncoding regions in a hereditary cancer panel. Genet Med 18, 1269–1275 (2016). PubMed PMC

Quang D, Chen Y & Xie X DANN: a deep learning approach for annotating the pathogenicity of genetic variants. Bioinformatics 31, 761–763 (2015). PubMed PMC

Ng PC & Henikoff S SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res 31, 3812–3814 (2003). PubMed PMC

Adzhubei IA, et al. A method and server for predicting damaging missense mutations. Nat Methods 7, 248–249 (2010). PubMed PMC

Schwarz JM, Rodelsperger C, Schuelke M & Seelow D MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods 7, 575–576 (2010). PubMed

Reva B, Antipin Y & Sander C Predicting the functional impact of protein mutations: application to cancer genomics. Nucleic Acids Res 39, e118 (2011). PubMed PMC

Lek M, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285–291 (2016). PubMed PMC

Kircher M, et al. A general framework for estimating the relative pathogenicity of human genetic variants. Nature Genetics 46, 310–+ (2014). PubMed PMC

van der Velde KJ, et al. GAVIN: Gene-Aware Variant INterpretation for medical sequencing. Genome Biol 18, 6 (2017). PubMed PMC

Liu X, Wu C, Li C & Boerwinkle E dbNSFP v3.0: A One-Stop Database of Functional Predictions and Annotations for Human Nonsynonymous and Splice-Site SNVs. Hum Mutat 37, 235–241 (2016). PubMed PMC

Gelb BD, et al. ClinGen’s RASopathy Expert Panel consensus methods for variant interpretation. Genet Med 20, 1334–1345 (2018). PubMed PMC

Duployez N, et al. Familial myeloid malignancies with germline TET2 mutation. Leukemia 34, 1450–1453 (2020). PubMed

Kaasinen E, et al. Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans. Nat Commun 10, 1252 (2019). PubMed PMC

Takaoka K, et al. A germline HLTF mutation in familial MDS induces DNA damage accumulation through impaired PCNA polyubiquitination. Leukemia 33, 1773–1782 (2019). PubMed

Buonocore F, et al. Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans. J Clin Invest (2017). PubMed PMC

Gohring G, et al. Complex karyotype newly defined: the strongest prognostic factor in advanced childhood myelodysplastic syndrome. Blood 116, 3766–3769 (2010). PubMed

Age-dependent phenotypic and molecular evolution of pediatric MDS arising from GATA2 deficiency

Molecular taxonomy of myelodysplastic syndromes and its clinical implications

Spontaneous remission and loss of monosomy 7: a window of opportunity for young children with SAMD9L syndrome