Germline SAMD9 and SAMD9L mutations are associated with extensive genetic evolution and diverse hematologic outcomes

Abstract

Germline SAMD9 and SAMD9L mutations cause a spectrum of multisystem disorders that carry a markedly increased risk of developing myeloid malignancies with somatic monosomy 7. Here, we describe 16 siblings, the majority of which were phenotypically normal, from 5 families diagnosed with myelodysplasia and leukemia syndrome with monosomy 7 (MLSM7; OMIM 252270) who primarily had onset of hematologic abnormalities during the first decade of life. Molecular analyses uncovered germline SAMD9L (n = 4) or SAMD9 (n = 1) mutations in these families. Affected individuals had a highly variable clinical course that ranged from mild and transient dyspoietic changes in the bone marrow to a rapid progression of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) with monosomy 7. Expression of these gain-of-function SAMD9 and SAMD9L mutations reduces cell cycle progression, and deep sequencing demonstrated selective pressure favoring the outgrowth of clones that have either lost the mutant allele or acquired revertant mutations. The myeloid malignancies of affected siblings acquired cooperating mutations in genes that are also altered in sporadic cases of AML characterized by monosomy 7. These data have implications for understanding how SAMD9 and SAMD9L mutations contribute to myeloid transformation and for recognizing, counseling, and treating affected families.

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.…”

Somatic mosaic monosomy 7 and UPD7q in a child with MIRAGE syndrome caused by a novel SAMD9 mutation

“…In some cases, uniparenteral disomy (UPD) as a true genetic reversion in SAMD9/9L genes with reduplication of the wild‐type allele was observed. This mechanism was noted in patients with transient monosomy 7 …”

In trans early mosaic mutational escape and novel phenotypic features of germline SAMD9 mutation

“…Functional somatic reversion through either loss of heterozygosity (−7 or 7q‐) or uniparental disomy (UPD), or through acquisition of loss of function (LOF) mutations, has been described in affected individuals. Thus far, LOF mutations have been described in cis for SAMD9 , but rarely in trans for SAMD9L (Nagata et al ., ; Wong et al ., ). Here we present a four‐generation pedigree affected by AML and MDS, with novel disease features and a reversion mutation in trans, consistent with germline mosaicism.…”