Year: 2017
Type: article
Study design: Case Report
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.
DOI: 10.1172/jci91913
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
Institutions: University College London, Stiftung Charité, Charité – Universitätsmedizin Berlin, Berlin-Brandenburger Centrum für Regenerative Therapien, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Alder Hey Children's NHS Foundation Trust, Alder Hey Children's Hospital, Northwick Park Hospital, University Hospital of Wales, University of Sheffield, The University of Queensland, Children's Health Queensland Hospital and Health Service, University of Pisa, University of Freiburg, University Medical Center Freiburg, German Cancer Research Center, Deutsches Konsortium für Translationale Krebsforschung, Max Delbrück Center, Great Ormond Street Hospital, Great Ormond Street Hospital for Children NHS Foundation Trust, Belfast City Hospital
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,501
Funders: Wellcome Trust, NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research, National Institute for Health and Care Research, Deutsche Forschungsgemeinschaft, Great Ormond Street Hospital for Children, Southern University of Science and Technology, Berlin Institute of Health, Medical Research Council, Great Ormond Street Institute of Child Health
OpenAlex ID: W2599756044