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


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 Buonocore F, Kühnen P, Suntharalingham JP, Del Valle I, Digweed M, Stachelscheid H, Khajavi N, Didi M, Brady AF, Blankenstein O, Procter AM, Dimitri P, Wales JKH, Ghirri P, Knöbl D, Strahm B, Erlacher M, Wlodarski MW, Chen W, Kokai GK, Anderson G, Morrogh D, Moulding DA, McKee SA, Niemeyer CM, Grüters A, Achermann JC
Journal The Journal of clinical investigation
Publication Date 2017 May 1;127(5):1700-1713
PubMed 28346228
PubMed Central PMC5409795
DOI 10.1172/jci91913

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