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

Several monogenic causes of familial myelodysplastic syndrome (MDS) have recently been identified. We studied two 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 two identified SAMD9L mutants decreased cell proliferation relative to wild-type protein. Of the ten individuals identified heterozygous for either SAMD9L mutation, three developed MDS upon loss of the mutated SAMD9L allele following intracellular infections associated with myeloid, B and NK cell deficiency. Five other individuals, three 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 cis SAMD9L truncating mutations. Examination of one 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 -γ induced SAMD9L expression. Clinically, revertant mosaicism was associated with milder disease, yet neurological manifestations persisted in three individuals. Two carriers also harbored a rare, in trans germline 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), where hematopoietic revertant mosaicism commonly ameliorated clinical manifestations. The findings suggest a role for SAMD9L in regulating IFN-driven, demand-adapted hematopoiesis.