Novel V1551L Mutation in SAMD9L Inhibits Cell Cycle Progression and Results in Pancytopenia That Progresses to MDS with Monosomy 7

Germline SAMD9L mutation is a recently recognized cause of constitutional bone marrow failure with a unique propensity for clonal evolution to myelodysplastic syndrome (MDS) with monosomy 7. It is now known that a clinical syndrome originally described in the 1970s as Ataxia-Pancytopenia Syndrome is caused by missense mutation in SAMD9L, and subsequent case series have demonstrated diverse clinical outcomes in patients with germline SAMD9L mutations. SAMD9L is located on chromosome 7, and gain-of-function mutations in SAMD9L is thought to decrease cell proliferation by inhibiting the normal cell cycle. In patients with SAMD9L mutations, the development of a monosomy 7 clone then rescues the inhibitory effect of mutant SAMD9L but can result in progression to acute leukemia. Interestingly, there are also reports of transient monosomy 7 due to uniparental disomy occurring in the monosomy 7 clone resulting in normal hematopoiesis. We describe the case of a male patient who presented at age 8-months of age with fever, hypotension, and pancytopenia. Bone marrow biopsy was hypocellular with debris-laden histiocytes. Diagnostic evaluation included normal chromosome stability testing (DEB and MMC), normal telomere length testing, and normal gene panels for inherited bone marrow failure and primary HLH. Patient, then, had spontaneous count recovery on day 41 of illness with progressive improvement becoming transfusion independent without any further infections. Repeat bone marrow biopsy 1 month after count recovery demonstrated dysplasia and cytogenetic evaluation revealed monosomy 7 in 11 out of 20 metaphases. Whole exome sequencing demonstrated a novel mutation in SAMD9L. Parents were analyzed for the SAMD9L mutation which were negative. Repeat bone marrow evaluation at 4, 7, and 10 months after presentation continued to demonstrate dysplasia and monosomy 7. After 12 months of observation, decision was made to perform a bone marrow transplant but the patient died from diffuse alveolar hemorrhage shortly after engraftment. EdU incorporation assay showed that 293T cells expressing SAMD9L V1551L mutation exhibit a cell cycle arrest phenotype as shown by the lack of cells in S phase compared to cells expressing the normal SAMD9L protein or empty vector. Furthermore, Digital droplet PCR (ddPCR) with wild type- and mutation-specific primers was used to quantify the percent of mutant allele in the patients' fibroblasts, whole blood, granulocytes, lymphocytes and lymphocy