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Myelodysplastic Syndromes
Constitutional SAMD9L mutations cause familial myelodysplastic syndrome and transient monosomy 7
Ferrata Storti Foundation
Victor B. Pastor,1,2* Sushree S. Sahoo,1,2,3* Jessica Boklan,4 Georg C. Schwabe,5 Ebru Saribeyoglu,5 Brigitte Strahm,1 Dirk Lebrecht,1 Matthias Voss,6 Yenan T. Bryceson,6 Miriam Erlacher,1,7 Gerhard Ehninger,8 Marena Niewisch,1 Brigitte Schlegelberger,9 Irith Baumann,10 John C. Achermann,11 Akiko Shimamura,12 Jochen Hochrein,13 Ulf Tedgård,14 Lars Nilsson,15 Henrik Hasle,16 Melanie Boerries,7,13 Hauke Busch,13,17 Charlotte M. Niemeyer1,7
and Marcin W. Wlodarski1,7
Haematologica 2018 Volume 103(3):427-437
1Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Germany; 2Faculty of Biology, University of Freiburg, Germany; 3Spemann Graduate School of Biology and Medicine, University of Freiburg, Germany; 4Center for Cancer and Blood Disorders, Phoenix Children's Hospital, AZ, USA; 5Children’s Hospital, Carl-Thiem-Klinikum Cottbus, Germany; 6Department of Medicine, Huddinge, Hematology and Regenerative Medicine, Karolinska Institute, Stockholm, Sweden; 7German Cancer Consortium (DKTK), Freiburg, Germany and German Cancer Research Center (DKFZ), Heidelberg, Germany; 8Internal Medicine of Hematology/Medical Oncology, University Hospital, Dresden, Germany; 9Institute of Human Genetics, Hannover Medical School, Germany; 10Clinical Centre South West, Department of Pathology, Böblingen Clinics, Germany; 11Genetics & Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, UK; 12Boston Children's Hospital, Dana Farber Cancer Institute, and Harvard Medical School, MA, USA; 13Institute of Molecular Medicine and Cell Research, University of Freiburg, Germany; 14Department of Pediatric Oncology and Hematology, Skåne University Hospital, Lund, Sweden; 15Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden; 16Department of Pediatrics, Aarhus University Hospital, Denmark and 17Lübeck Institute of Experimental Dermatology, Germany
*VBP and SS contributed equally to this manuscript.
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 medi- an 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 fre- quency 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 pro- gression 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.
Correspondence:
marcin.wlodarski@uniklinik-freiburg.de
Received: September 12, 2017. Accepted: December 5, 2017. Pre-published: December 7, 2017.
doi:10.3324/haematol.2017.180778
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/3/427
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haematologica | 2018; 103(3)
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