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Germline mutations in the SAMD9 and SAMD9L genes, located in tandem on chromosome 7, are associated with a clinical spectrum of disorders including the MIRAGE syndrome, ataxia-pancytopenia syndrome and myelodysplasia and leukemia syndrome with monosomy 7 syndrome. Germline gain-of-function mutations increase SAMD9 or SAMD9L's normal antiproliferative effect. This causes pancytopenia and generally restricted growth and/or specific organ hypoplasia in non-hematopoietic tissues. In blood cells, additional somatic aberrations that reverse the germline mutation's effect, and give rise to the clonal expansion of cells with reduced or no antiproliferative effect of SAMD9 or SAMD9L include complete or partial chromosome 7 loss or loss-of-function mutations in SAMD9 or SAMD9L. Furthermore, the complete or partial loss of chromosome 7q may cause myelodysplastic syndrome in these patients. SAMD9 mutations appear to associate with a more severe disease phenotype, including intrauterine growth restriction, developmental delay and hypoplasia of adrenal glands, testes, ovaries or thymus, and most reported patients died in infancy or early childhood due to infections, anemia and/or hemorrhages. SAMD9L mutations have been reported in a few families with balance problems and nystagmus due to cerebellar atrophy, and may lead to similar hematological disease as seen in SAMD9 mutation carriers, from early childhood to adult years. We review the clinical features of these syndromes, discuss the underlying biology, and interpret the genetic findings in some of the affected family members. We provide expert-based recommendations regarding diagnosis, follow-up, and treatment of mutation carriers.

SAMD9 and SAMD9L in inherited predisposition to ataxia, pancytopenia, and myeloid malignancies