Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes

Germline SAMD9 and SAMD9L mutations (SAMD9/9L^mut) 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 SAMD9/9L^mut accounted for 8% and were mutually exclusive with GATA2 mutations present in 7% of the cohort. Among SAMD9/9L^mut 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 SAMD9/9L^mut clustering to protein middle regions. Despite inconclusive in silico prediction, 94% of SAMD9/9L^mut suppressed HEK293 cell growth, and mutations expressed in CD34⁺ cells induced overt cell death. Furthermore, we found that 61% of SAMD9/9L^mut 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 SAMD9/9L^mut). Finally, bone marrow single-cell DNA sequencing revealed multiple competing SGR events in individual patients. Our findings demonstrate that SGR is common in SAMD9/9L^mut MDS and exemplify the exceptional plasticity of hematopoiesis in children.

Sahoo S.S., Victor B. Pastor, Charnise Goodings, Rebecca K. Voss, Emilia J. Kozyra, Amina Szvetnik, Peter Noellke, Michael Dworzak, Jan Starý, Franco Locatelli, Riccardo Masetti, Markus Schmugge, Barbara De Moerloose, Albert Catala, Krisztián Kállay, Dominik Turkiewicz, Henrik Hasle, Jochen Buechner, Kirsi Jahnukainen, Marek Ussowicz, Sophia Polychronopoulou, Owen P. Smith, Oksana Fabri, Shlomit Barzilai, Valerie de Haas, Irith Baumann, Stephan Schwarz-Furlan, the European Working Group of MDS in Children (EWOG-MDS), Marena R. Niewisch, Martin G. Sauer, Birgit Burkhardt, Peter Lang, Peter Bader, Rita Beier, Ingo Müller, Michael H. Albert, Roland Meisel, Ansgar Schulz, Gunnar Cario, Pritam K. Panda, Julius Wehrle, Shinsuke Hirabayashi, Marta Derecka, Robert Durruthy-Durruthy, Gudrun Göhring, Ayami Yoshimi-Noellke, Manching Ku, Dirk Lebrecht, Miriam Erlacher, Christian Flotho, Brigitte Strahm, Charlotte M. Niemeyer, Marcin W. Wlodarski