Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans
Federica Buonocore, … , Annette Grüters, John C. Achermann
Federica Buonocore, … , Annette Grüters, John C. Achermann
Published March 27, 2017
Citation Information: J Clin Invest. 2017;127(5):1700-1713. https://doi.org/10.1172/JCI91913.
View: Text | PDF
Research Article Endocrinology Genetics

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.

Authors

Federica Buonocore, Peter Kühnen, Jenifer P. Suntharalingham, Ignacio Del Valle, Martin Digweed, Harald Stachelscheid, Noushafarin Khajavi, Mohammed Didi, Angela F. Brady, Oliver Blankenstein, Annie M. Procter, Paul Dimitri, Jerry K.H. Wales, Paolo Ghirri, Dieter Knöbl, Brigitte Strahm, Miriam Erlacher, Marcin W. Wlodarski, Wei Chen, George K. Kokai, Glenn Anderson, Deborah Morrogh, Dale A. Moulding, Shane A. McKee, Charlotte M. Niemeyer, Annette Grüters, John C. Achermann

×

Figure 3

Acquired loss of chromosome 7 (–7) and its long arm (7q–) occurred in association with a reduction in the gain-of-function SAMD9 mutations.

Options: View larger image (or click on image) Download as PowerPoint
Acquired loss of chromosome 7 (–7) and its long arm (7q–) occurred in as...
(A) Chromatograms (top) from all 8 patients showing the SAMD9 mutations and a reduction in the mutant peak following development of monosomy 7 as shown by cytogenomic array (bottom). All samples are from peripheral leukocytes except the later sample in patient 4, which is from bone marrow DNA. Typical disomic chromosome 7 signal is shown in blue, whereas the signal with monosomy is shown in green. Data are presented in relation to length of survival. For patients 4–6 the earlier array is shown on the left and the later array on the right. The age at sampling is shown above the figure. BMT, bone marrow transplantation; IUD, intrauterine death; mo, months. (B) Serial cytogenetic data (leukocytes) from patient 6 showing the expansion of cells with –7 followed by their displacement by a 7q– clone removing the locus containing the SAMD9 gene. (C) Serial changes in the WT and mutant allele percentage (%) in patient 6 show that –7/7q– is associated with a reduction of the mutant SAMD9 allele, most likely due to the growth selection advantage of bone marrow cells that have lost the growth-repressing mutation. Data are derived from single-nucleotide primer extension assays for leukocyte DNA. A similar reduction in mutant allele was found in other patients who developed –7/7q– (patients 4 and 5) or who presented with a –7/7q– clone at the time of diagnosis of MDS (patients 7 and 8) (Table 1 and Supplemental Figures 3 and 4).