2. Academic Validation
  3. Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms

Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms

  • Blood. 2017 Apr 20;129(16):2266-2279. doi: 10.1182/blood-2016-10-743302.
Bianca Tesi 1 2 3 4,  Josef Davidsson 5 6,  Matthias Voss 1,  Elisa Rahikkala 7 8,  Tim D Holmes 1 9,  Samuel C C Chiang 1,  Jonna Komulainen-Ebrahim 7 10,  Sorina Gorcenco 11,  Alexandra Rundberg Nilsson 5,  Tim Ripperger 12,  Hannaleena Kokkonen 13,  David Bryder 5,  Thoas Fioretos 14,  Jan-Inge Henter 2,  Merja Möttönen 7 10,  Riitta Niinimäki 7 10,  Lars Nilsson 15,  Cornelis Jan Pronk 5 6,  Andreas Puschmann 11,  Hong Qian 1,  Johanna Uusimaa 7 10,  Jukka Moilanen 7 8,  Ulf Tedgård 6,  Jörg Cammenga 5 16 17,  Yenan T Bryceson 1 9
Affiliations

Affiliations

  • 1 Centre for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
  • 2 Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
  • 3 Division of Pediatrics, and.
  • 4 Clinical Genetics Unit, Department of Molecular Medicine and Surgery, and Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
  • 5 Division of Molecular Hematology, Institution for Laboratory Medicine, Lund University, Lund, Sweden.
  • 6 Department of Pediatric Oncology and Hematology, Skåne University Hospital, Lund, Sweden.
  • 7 PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu, Oulu, Finland.
  • 8 Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland.
  • 9 Broegelmann Research Laboratory, Department of Clinical Sciences, University of Bergen, Bergen, Norway.
  • 10 Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland.
  • 11 Department of Neurology, Lund University, Lund, Sweden.
  • 12 Department of Human Genetics, Hannover Medical School, Hannover, Germany.
  • 13 Department of Clinical Chemistry, Oulu University Hospital, Oulu, Finland.
  • 14 Department of Clinical Genetics, Lund University, Lund, Sweden.
  • 15 Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden.
  • 16 Department of Hematology, Linköping University Hospital, Linköping, Sweden; and.
  • 17 Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
PMID: 28202457 DOI: 10.1182/blood-2016-10-743302
Abstract

Several monogenic causes of familial myelodysplastic syndrome (MDS) have recently been identified. We studied 2 families with cytopenia, predisposition to MDS with chromosome 7 aberrations, immunodeficiency, and progressive cerebellar dysfunction. Genetic studies uncovered heterozygous missense mutations in SAMD9L, a tumor suppressor gene located on chromosome arm 7q. Consistent with a gain-of-function effect, ectopic expression of the 2 identified SAMD9L mutants decreased cell proliferation relative to wild-type protein. Of the 10 individuals identified who were heterozygous for either SAMD9L mutation, 3 developed MDS upon loss of the mutated SAMD9L allele following intracellular infections associated with myeloid, B-, and natural killer (NK)-cell deficiency. Five other individuals, 3 with spontaneously resolved cytopenic episodes in infancy, harbored hematopoietic revertant mosaicism by uniparental disomy of 7q, with loss of the mutated allele or additional in cisSAMD9L truncating mutations. Examination of 1 individual indicated that somatic reversions were postnatally selected. Somatic mutations were tracked to CD34+ hematopoietic progenitor cell populations, being further enriched in B and NK cells. Stimulation of these cell types with interferon (IFN)-α or IFN-γ induced SAMD9L expression. Clinically, revertant mosaicism was associated with milder disease, yet neurological manifestations persisted in 3 individuals. Two carriers also harbored a rare, in trans germ line SAMD9L missense loss-of-function variant, potentially counteracting the SAMD9L mutation. Our results demonstrate that gain-of-function mutations in the tumor suppressor SAMD9L cause cytopenia, immunodeficiency, variable neurological presentation, and predisposition to MDS with -7/del(7q), whereas hematopoietic revertant mosaicism commonly ameliorated clinical manifestations. The findings suggest a role for SAMD9L in regulating IFN-driven, demand-adapted hematopoiesis.

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