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Author(s): Sushree S. Sahoo [sup.1] [sup.2] , Victor B. Pastor [sup.2] , Charnise Goodings [sup.1] , Rebecca K. Voss [sup.2] , Emilia J. Kozyra [sup.2] [sup.3] , Amina Szvetnik [sup.2] [...], Germline SAMD9 and SAMD9L mutations (SAMD9/9L.sup.mut) predispose to myelodysplastic syndromes (MDS) with propensity for somatic rescue. In this study, we investigated a clinically annotated pediatric MDS cohort (n = 669) to define the prevalence, genetic landscape, phenotype, therapy outcome and clonal architecture of SAMD9/9L syndromes. In consecutively diagnosed MDS, germline SAMD9/9L.sup.mut accounted for 8% and were mutually exclusive with GATA2 mutations present in 7% of the cohort. Among SAMD9/9L.sup.mut cases, refractory cytopenia was the most prevalent MDS subtype (90%); acquired monosomy 7 was present in 38%; constitutional abnormalities were noted in 57%; and immune dysfunction was present in 28%. The clinical outcome was independent of germline mutations. In total, 67 patients had 58 distinct germline SAMD9/9L.sup.mut clustering to protein middle regions. Despite inconclusive in silico prediction, 94% of SAMD9/9L.sup.mut suppressed HEK293 cell growth, and mutations expressed in CD34.sup.+ cells induced overt cell death. Furthermore, we found that 61% of SAMD9/9L.sup.mut patients underwent somatic genetic rescue (SGR) resulting in clonal hematopoiesis, of which 95% was maladaptive (monosomy 7 [plus or minus] cancer mutations), and 51% had adaptive nature (revertant UPD7q, somatic SAMD9/9L.sup.mut). Finally, bone marrow single-cell DNA sequencing revealed multiple competing SGR events in individual patients. Our findings demonstrate that SGR is common in SAMD9/9L.sup.mut MDS and exemplify the exceptional plasticity of hematopoiesis in children. This analysis of a large, clinically annotated cohort of individuals with predisposition to myelodysplastic syndromes reveals insights into the genetic determinants of disease progression and their relationship with clinical manifestations and therapy outcome.

Familial myelodysplastic syndromes arise from haploinsufficiency of genes involved in hematopoiesis and are primarily associated with early-onset disease. Here we describe a familial syndrome in seven patients from four unrelated pedigrees presenting with myelodysplastic syndrome and loss of chromosome 7/7q. Their median age at diagnosis was 2.1 years (range, 1-42). All patients presented with thrombocytopenia with or without additional cytopenias and a hypocellular marrow without an increase of blasts. Genomic studies identified constitutional mutations (p.H880Q, p.R986H, p.R986C and p.V1512M) in the SAMD9L gene on 7q21, with decreased allele frequency in hematopoiesis. The non-random loss of mutated SAMD9L alleles was attained via monosomy 7, deletion 7q, UPD7q, or acquired truncating SAMD9L variants p.R1188X and p.S1317RfsX21. Incomplete penetrance was noted in 30% (3/10) of mutation carriers. Long-term observation revealed divergent outcomes with either progression to leukemia and/or accumulation of driver mutations (n=2), persistent monosomy 7 (n=4), and transient monosomy 7 followed by spontaneous recovery with SAMD9L -wildtype UPD7q (n=2). Dysmorphic features or neurological symptoms were absent in our patients, pointing to the notion that myelodysplasia with monosomy 7 can be a sole manifestation of SAMD9L disease. Collectively, our results define a new subtype of familial myelodysplastic syndrome and provide an explanation for the phenomenon of transient monosomy 7. Registered at: www.clinicaltrials.gov; #NCT00047268 ., (Copyright© 2018 Ferrata Storti Foundation.)