Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms PMID: 28202457

Target-related Cytokines

2026-09-23

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

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.

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.