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

B Tesi, J Davidsson, M Voss… - Blood, The Journal …, 2017 - ashpublications.org
B Tesi, J Davidsson, M Voss, E Rahikkala, TD Holmes, SCC Chiang, J Komulainen-Ebrahim…
Blood, The Journal of the American Society of Hematology, 2017ashpublications.org
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 …
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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