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

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Item Type:Article
Title:Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans
Creators Name:Buonocore, F. and Kuehnen, P. and Suntharalingham, J.P. and Del Valle, I. and Digweed, M. and Stachelscheid, H. and Khajavi, N. and Didi, M. and Brady, A.F. and Blankenstein, O. and Procter, A.M. and Dimitri, P. and Wales, J.K.H. and Ghirri, P. and Knoebl, D. and Strahm, B. and Erlacher, M. and Wlodarski, M.W. and Chen, W. and Kokai, G.K. and Anderson, G. and Morrogh, D. and Moulding, D.A. and McKee, S. A. and Niemeyer, C.M. and Grueters, A. and Achermann, J.C.
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 {alpha} 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.
Keywords:Adrenal Insufficiency, Chromosome Deletion, Cohort Studies, Frameshift Mutation, Haploinsufficiency, Myelodysplastic Syndromes, Pair 7 Human Chromosomes, Proteins
Source:Journal of Clinical Investigation
Publisher:American Society for Clinical Investigation
Page Range:1700-1713
Date:1 May 2017
Additional Information:Copyright © 2017 Buonocore et al.
Official Publication:https://doi.org/10.1172/JCI91913
PubMed:View item in PubMed

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