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

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

doi:10.1172/jci91913

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.

Highlights

Sterile α motif domain–containing protein 9 (SAMD9, OMIM 610456) is a 1,589–amino acid protein that is encoded by a gene on the long arm of chromosome 7 (7q21.2) [1]
Using quantitative reverse transcriptase PCR of human fetal and adult tissues, SAMD9 expression was highest in the fetal adrenal gland, with high expression in the colon, bone marrow, fetal liver, thymus, spleen, lung, liver, and fetal testis (Figure 2B)
Using a combination of whole-exome sequencing and targeted capture, we have identified a severe multisystem disorder caused by heterozygous SAMD9 mutations in eight 46,XY patients with marked intrauterine growth restriction (IUGR), severe testicular dysfunction, congenital adrenal insufficiency, thrombocytopenia/anemia, persistent diarrhea, and severe infections resulting in a life-threatening course

Summary

Introduction

Sterile α motif domain–containing protein 9 (SAMD9, OMIM 610456) is a 1,589–amino acid protein that is encoded by a gene on the long arm of chromosome 7 (7q21.2) [1]. Heterozygous gain-of-function mutations in SAMD9 have been reported in 11 patients with IUGR, adrenal insufficiency, and gonadal failure, together with bone marrow failure [15]. Two of these patients had monosomy 7 and developed MDS. This condition has been termed MIRAGE syndrome (myelodysplasia, infections, restriction of growth, adrenal hypoplasia, genital phenotypes, enteropathy) (OMIM 617053). We are able to show, for the first time to our knowledge, that complex dynamic somatic changes in SAMD9 and the SAMD9/SAMD9L locus on chromosome 7q occur, which are associated with this distinct disease phenotype and modify survival in these patients

Results

Discussion

Findings

Methods