Noncoding copy-number variations are associated with congenital limb malformation |
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| Affiliation: | 1. Max Planck Institute for Molecular Genetics, Berlin, Germany;;2. Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany;;3. Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland;;4. Gemeinschaftspraxis für Humangenetik Homburg/Saar, Homburg, Germany;;5. Department of Physiology, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka;;6. Institute of Human Genetics, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany;;7. Institute of Human Genetics, RWTH Aachen, Aachen, Germany;;8. Raphael Recanati Genetics Institute, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel;;9. Instituto de Genética Médica y Molecular, IdiPAZ, Hospital Universitario La Paz, Madrid, Spain;;10. U753 Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain;;11. Handchirurgie Kinderkrankenhaus Wilhelmstift, Hamburg, Germany;;12. Institute of Human Genetics, Biocentre, University of Würzburg, Würzburg, Germany;;13. Merseyside and Cheshire Regional Molecular Genetics Laboratory, Liverpool Women’s National Health Service Foundation Trust, Liverpool, UK;;14. Institute of Human Genetics, University of Ulm, Ulm, Germany;;15. Department of Clinical Genetics, Children’s Hospital at Westmead, and Disciplines of Paediatrics and Child Health and Genetic Medicine, University of Sydney, New South Wales, Australia;;16. Department of Genetics and Evolution, University of Geneva, Geneva, Switzerland;;17. School of Life Sciences, Federal Institute of Technology, Lausanne, Switzerland;;18. Department of Genome Sciences, University of Washington, Seattle, USA. |
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| Abstract: | PurposeCopy-number variants (CNVs) are generally interpreted by linking the effects of gene dosage with phenotypes. The clinical interpretation of noncoding CNVs remains challenging. We investigated the percentage of disease-associated CNVs in patients with congenital limb malformations that affect noncoding cis-regulatory sequences versus genes sensitive to gene dosage effects.MethodsWe applied high-resolution copy-number analysis to 340 unrelated individuals with isolated limb malformation. To investigate novel candidate CNVs, we re-engineered human CNVs in mice using clustered regularly interspaced short palindromic repeats (CRISPR)–based genome editing.ResultsOf the individuals studied, 10% harbored CNVs segregating with the phenotype in the affected families. We identified 31 CNVs previously associated with congenital limb malformations and four novel candidate CNVs. Most of the disease-associated CNVs (57%) affected the noncoding cis-regulatory genome, while only 43% included a known disease gene and were likely to result from gene dosage effects. In transgenic mice harboring four novel candidate CNVs, we observed altered gene expression in all cases, indicating that the CNVs had a regulatory effect either by changing the enhancer dosage or altering the topological associating domain architecture of the genome.ConclusionOur findings suggest that CNVs affecting noncoding regulatory elements are a major cause of congenital limb malformations. |
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