Constitutional SAMD9L mutations cause familial myelodysplastic syndrome and transient monosomy 7

Abstract

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.

Outcomes of Hematopoietic Cell Transplantation in Patients with Germline SAMD9/SAMD9L Mutations

“…Twelve patients underwent allogeneic HCT for hematologic disorders associated with germline SAMD9 (n = 6) or SAMD9L (n = 6) mutations ( Table 1). Patients 3,4,6,11,and 12 (Table 1) were included in previous reports [11,13,17]. Indication for transplant was MDS in 10 of 12 (83%) cases.…”

“…Gain-of-function heterozygous mutations in these genes lead to cellular growth restriction and hypoplasia, resulting in cytopenias, bone marrow failure, and immunodeficiency. Interestingly, in many cases, there is a nonrandom loss of the mutated allele via full or partial deletion of chromosome 7 [4,[10][11][12]. The resultant monosomy 7 or deletion 7q can result in the development of MDS and acute myeloid leukemia (AML) [8,11,12].…”

“…Interestingly, in many cases, there is a nonrandom loss of the mutated allele via full or partial deletion of chromosome 7 [4,[10][11][12]. The resultant monosomy 7 or deletion 7q can result in the development of MDS and acute myeloid leukemia (AML) [8,11,12]. Conversely, other "genetic correction" events such as in cis missense, nonsense, or loss of heterozygosity through uniparental disomy can result in normal hematopoiesis.…”

“…Since the initial report of MIRAGE syndrome in 2016, a series of studies has described clinical and genetic findings in patients and families with SAMD9/SAMD9L mutations [7,11,13]. Hematopoietic cell transplantation (HCT) therapy has been included in some reports, but transplantation details are lacking.…”

A novel SAMD9 variant identified in patient with MIRAGE syndrome: Further defining syndromic phenotype and review of previous cases

“…Recent reports from Pastor et al and Wong et al discussed patients with SAMD9 and sterile α motif domain‐containing protein 9‐like ( SAMD9L ) mutations with myelodysplastic syndrome (MDS), some of which they observed to have transient monosomy 7 as well. They suggested that the transient monosomy occurred “as a one‐time clonal event followed by somatic correction of hematopoiesis achieved by uniparental disomy for chromosome 7q (UPD7q) with double wild‐type SAMD9L .” Additional reports have also previously documented transient monosomy 7 in pediatric patients with MDS …”