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.
| Original language | English |
|---|---|
| Journal | Genetics in Medicine |
| Volume | 20 |
| Issue number | 6 |
| Pages (from-to) | 599-607 |
| Number of pages | 9 |
| ISSN | 1098-3600 |
| DOIs | |
| Publication status | Published - 01.06.2018 |
Funding
599 607 10.1038/gim.2017.154 EN Ricarda Flöttmann Max Planck Institute for Molecular Genetics, Berlin, Germany Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany Bjørt K Kragesteen Max Planck Institute for Molecular Genetics, Berlin, Germany Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany Sinje Geuer Max Planck Institute for Molecular Genetics, Berlin, Germany Magdalena Socha Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland Lila Allou Max Planck Institute for Molecular Genetics, Berlin, Germany Anna Sowińska-Seidler Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland Laure Bosquillon de Jarcy Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany Johannes Wagner Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany Aleksander Jamsheer Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland Barbara Oehl-Jaschkowitz Gemeinschaftspraxis für Humangenetik Homburg/Saar, Homburg, Germany Lars Wittler Max Planck Institute for Molecular Genetics, Berlin, Germany Deepthi de Silva Department of Physiology, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka Ingo Kurth Institute of Human Genetics, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany Institute of Human Genetics, RWTH Aachen, Aachen, Germany Idit Maya Raphael Recanati Genetics Institute, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel Fernando Santos-Simarro Instituto de Genética Médica y Molecular, IdiPAZ, Hospital Universitario La Paz, Madrid, Spain U753 Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain Wiebke Hülsemann Handchirurgie Kinderkrankenhaus Wilhelmstift, Hamburg, Germany Eva Klopocki Institute of Human Genetics, Biocentre, University of Würzburg, Würzburg, Germany Roger Mountford Merseyside and Cheshire Regional Molecular Genetics Laboratory, Liverpool Women’s National Health Service Foundation Trust, Liverpool, UK Alan Fryer Merseyside and Cheshire Regional Molecular Genetics Laboratory, Liverpool Women’s National Health Service Foundation Trust, Liverpool, UK Guntram Borck Institute of Human Genetics, University of Ulm, Ulm, Germany Denise Horn Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany Pablo Lapunzina Instituto de Genética Médica y Molecular, IdiPAZ, Hospital Universitario La Paz, Madrid, Spain Meredith Wilson 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 Bénédicte Mascrez Department of Genetics and Evolution, University of Geneva, Geneva, Switzerland Denis Duboule Department of Genetics and Evolution, University of Geneva, Geneva, Switzerland School of Life Sciences, Federal Institute of Technology, Lausanne, Switzerland Stefan Mundlos Max Planck Institute for Molecular Genetics, Berlin, Germany Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany Malte Spielmann Max Planck Institute for Molecular Genetics, Berlin, Germany Department of Genome Sciences, University of Washington, Seattle, USA gim2017154 10.1038/gim.2017.154 2017 4 12 2017 7 11 2017 10 12 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.
UN SDGs
This output contributes to the following UN Sustainable Development Goals (SDGs)
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SDG 3 Good Health and Well-being -
SDG 10 Reduced Inequalities
Research Areas and Centers
- Research Area: Medical Genetics
- Centers: Center for Rare Diseases (ZSE)
DFG Research Classification Scheme
- 2.22-03 Human Genetics
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