Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans

Abstract

It is well established that somatic genomic changes can influence phenotypes in cancer, but the role of adaptive changes in developmental disorders is less well understood. Here we have used next-generation sequencing approaches to identify de novo heterozygous mutations in sterile α motif domain–containing protein 9 (SAMD9, located on chromosome 7q21.2) in 8 children with a multisystem disorder termed MIRAGE syndrome that is characterized by intrauterine growth restriction (IUGR) with gonadal, adrenal, and bone marrow failure, predisposition to infections, and high mortality. These mutations result in gain of function of the growth repressor product SAMD9. Progressive loss of mutated SAMD9 through the development of monosomy 7 (–7), deletions of 7q (7q–), and secondary somatic loss-of-function (nonsense and frameshift) mutations in SAMD9 rescued the growth-restricting effects of mutant SAMD9 proteins in bone marrow and was associated with increased length of survival. However, 2 patients with –7 and 7q– developed myelodysplastic syndrome, most likely due to haploinsufficiency of related 7q21.2 genes. Taken together, these findings provide strong evidence that progressive somatic changes can occur in specific tissues and can subsequently modify disease phenotype and influence survival. Such tissue-specific adaptability may be a more common mechanism modifying the expression of human genetic conditions than is currently recognized.

Two patients with MIRAGE syndrome lacking haematological features: role of somatic second-site reversion SAMD9 mutations

“…In the report by Buonocore et al , two out of four patients with two mutations died very early, and the remaining two patients developed myelodysplastic syndrome with monosomy 7 3. Probably due to these reasons, the proportion of the revertant cells did not reach to 100% 3. Hence, the two patients described in this study are the first patients who achieved complete haematological reversion.…”

“…For patient 2, although we could not test whether p.Gln39* was a somatic mutation since the patient has already died, skewed X chromosome inactivation in leucocytes was shown, indicating their monoclonality. Simultaneous detection of one activating and another inactivating SAMD9 mutation in MIRAGE syndrome have already been reported by Buonocore et al ,3 although colocalisation of two mutations on the same allele was not confirmed. In the report by Buonocore et al , two out of four patients with two mutations died very early, and the remaining two patients developed myelodysplastic syndrome with monosomy 7 3.…”

“…Simultaneous detection of one activating and another inactivating SAMD9 mutation in MIRAGE syndrome have already been reported by Buonocore et al ,3 although colocalisation of two mutations on the same allele was not confirmed. In the report by Buonocore et al , two out of four patients with two mutations died very early, and the remaining two patients developed myelodysplastic syndrome with monosomy 7 3. Probably due to these reasons, the proportion of the revertant cells did not reach to 100% 3.…”

Myeloid Neoplasms with Germline Predisposition

“…Schwartz et al [42] identified these mutations in 17% of pediatric MDS patients. Germline variants in SAMD9 and SAMD9L have been associated with multisystem disorders with a range of systemic abnormalities, including cytopenia, infection, intrauterine restriction of growth, adrenal hypoplasia, abnormal genital phenotypes, progressive cerebellar dysfunction, and enteropathy [43][44][45][46]. To date, there are no reports of expected BM morphology in mutation carriers.…”

Familial myelodysplastic syndrome/acute myeloid leukemia

“…The genes implicated are diverse, including well-known hematopoietic transcription factors such as CEBPA, GATA2, and RUNX1 as well as genes such as BRCA1 and MSH6 , more traditionally thought of as solid tumor risk genes [10]. The most recently identified genes, DDX41, SAMD9 and SAMD9L , are revealing novel pathways involved in leukemogenesis and deepening our understanding of the basic biology of MDS/AML [11–13]. In recognition of the impact of this growing field on clinical care, the World Health Organization, European Leukemia Net, and National Comprehensive Cancer Network have all recently incorporated consideration of MDS/AML germ line predisposition syndromes into MDS/AML classification and clinical management guidelines, making knowledge of these syndromes now essential for clinicians and pathologists alike [14–16].…”