Constitutional SAMD9L mutations cause familial myelodysplastic syndrome and transient monosomy 7

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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:; #NCT00047268.


  • 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
  • Lars Nilsson
  • Henrik Hasle
  • Melanie Boerries
  • Hauke Busch
  • Charlotte M. Niemeyer
  • Marcin W. Wlodarski
External organisations
  • Albert-Ludwigs University Freiburg
  • Karolinska Institutet
  • German Cancer Research Centre
  • Medizinsche Klinik und Poliklinik I, Dresden
  • Hannover Medical School
  • University College London
  • Boston Children's Hospital
  • Skåne University Hospital
  • Aarhus University Hospital
  • Phoenix Children’s Hospital
  • Carl-Thiem-Klinikum Cottbus
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Hematology
Original languageEnglish
Pages (from-to)427-437
Issue number3
Publication statusPublished - 2018 Feb 28
Publication categoryResearch
Externally publishedYes