Balanced chromosomal rearrangements offer insights into coding and noncoding genomic features associated with developmental disorders
Abstract
ABSTRACT Balanced chromosomal rearrangements (BCRs), including inversions, translocations, and insertions, reorganize large sections of the genome and contribute substantial risk for developmental disorders (DDs). However, the rarity and lack of systematic screening for BCRs in the population has precluded unbiased analyses of the genomic features and mechanisms associated with risk for DDs versus normal developmental outcomes. Here, we sequenced and analyzed 1,420 BCR breakpoints across 710 individuals, including 406 DD cases and the first large-scale collection of 304 control BCR carriers. We found that BCRs were not more likely to disrupt genes in DD cases than controls, but were seven-fold more likely to disrupt genes associated with dominant DDs (21.3% of cases vs. 3.4% of controls; P = 1.60×10 −12 ). Moreover, BCRs that did not disrupt a known DD gene were significantly enriched for breakpoints that altered topologically associated domains (TADs) containing dominant DD genes in cases compared to controls (odds ratio [OR] = 1.43, P = 0.036). We discovered six TADs enriched for noncoding BCRs (false discovery rate < 0.1) that contained known DD genes ( MEF2C, FOXG1, SOX9, BCL11A, BCL11B , and SATB2 ) and represent candidate pathogenic long-range positional effect (LRPE) loci. These six TADs were collectively disrupted in 7.4% of the DD cohort. Phased Hi-C analyses of five cases with noncoding BCR breakpoints localized to one of these putative LRPEs, the 5q14.3 TAD encompassing MEF2C , confirmed extensive disruption to local 3D chromatin structures and reduced frequency of contact between the MEF2C promoter and annotated enhancers. We further identified six genomic features enriched in TADs preferentially disrupted by noncoding BCRs in DD cases versus controls and used these features to build a model to predict TADs at risk for LRPEs across the genome. These results emphasize the potential impact of noncoding structural variants to cause LRPEs in unsolved DD cases, as well as the complex interaction of features associated with predicting three-dimensional chromatin structures intolerant to disruption.
Authors 99
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Broad Institute · Harvard University · Massachusetts General Hospital
Affiliation as printed
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
Department of Neurology, Harvard Medical School, Boston, MA, USA
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Boston, MA, USA
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Affiliation as printed
Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
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Broad Institute · Harvard University · Massachusetts General Hospital
Affiliation as printed
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
Program in Bioinformatics and Integrative Genomics, Division of Medical Sciences, Harvard Medical School, Boston, MA, USA
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Boston, MA, USA
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Affiliation as printed
Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
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Baylor College of Medicine · Center for Theoretical Biological Physics · Rice University
Affiliation as printed
Center for Theoretical Biological Physics and Department of Computer Science, Rice University, Houston, TX 77030, USA
The Center for Genome Architecture, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Center for Theoretical Biological Physics and Department of Computer Science, Rice University, Houston, TX 030, USA
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Broad Institute · Harvard University · Massachusetts General Hospital
Affiliation as printed
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
Department of Neurology, Harvard Medical School, Boston, MA, USA
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Boston, MA, USA
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Chinese University of Hong Kong
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Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, China
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University of Copenhagen · Copenhagen University Hospital · Rigshospitalet
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Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
Department of Clinical Genetics, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
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Baylor College of Medicine · Center for Theoretical Biological Physics · Rice University
Affiliation as printed
Center for Theoretical Biological Physics and Department of Computer Science, Rice University, Houston, TX 77030, USA
The Center for Genome Architecture, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Center for Theoretical Biological Physics and Department of Computer Science, Rice University, Houston, TX 030, USA
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Baylor College of Medicine · Center for Theoretical Biological Physics · Rice University
Affiliation as printed
Center for Theoretical Biological Physics and Department of Computer Science, Rice University, Houston, TX 77030, USA
The Center for Genome Architecture, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Center for Theoretical Biological Physics and Department of Computer Science, Rice University, Houston, TX 030, USA
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Affiliation as printed
Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
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Affiliation as printed
Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
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Affiliation as printed
Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
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Affiliation as printed
Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
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Affiliation as printed
Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
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Mental Health Services · Copenhagen University Hospital
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Institute of Biological Psychiatry, Mental Health Services, Copenhagen University Hospital, Copenhagen, Denmark
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Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
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Affiliation as printed
Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
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Affiliation as printed
Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
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University of Helsinki · Finnish Institute for Health and Welfare
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Department of Medical Genetics, University of Helsinki, Helsinki, Finland
Population Health Unit, Department of Public Health and Welfare, National Institute for Health and Welfare, Helsinki, Finland
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Finnish Institute for Health and Welfare · Institute for Molecular Medicine Finland
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Institute for Molecular Medicine Finland (FIMM), Biomedicum 2U, Helsinki, Finland
Population Health Unit, Department of Public Health and Welfare, National Institute for Health and Welfare, Helsinki, Finland
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Maastricht University Medical Centre · Maastricht University
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Maastricht University Medical Center, Maastricht, Netherlands
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Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil
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Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil
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Faculdade de Medicina, Universidade de Brasília, Brasília, Brazil
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Faculdade de Medicina, Universidade de Brasília, Brasília, Brazil
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Sarah Network of Rehabilitation Hospitals
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Cytogenetic Laboratory Molecular Pathology, SARAH Network of Rehabilitation Hospitals, Brasília, Brazil
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Center for Human Genetics, KU Leuven, Leuven, Belgium
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Center for Human Genetics, KU Leuven, Leuven, Belgium
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Cyprus Institute of Neurology and Genetics
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Department of Cytogenetics and Genomics, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
The Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
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Cyprus Institute of Neurology and Genetics
Affiliation as printed
Department of Cytogenetics and Genomics, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
The Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
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Cyprus Institute of Neurology and Genetics
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Department of Cytogenetics and Genomics, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
The Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
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Institute of Medical Genetics, University of Zurich, Schlieren, Switzerland
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Hospices Civils de Lyon · Institut NeuroMyoGène
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Institut NeuroMyoGene, Université Claude Bernard Lyon, Bron, France
Service de Génétique, Hospices Civils de Lyon, Groupement Hospitalier Universitaire, Bron, France
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Service de Génétique, Hospices Civils de Lyon, Groupement Hospitalier Universitaire, Bron, France
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Max Planck Institute for Molecular Genetics
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Group Development and Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany
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Genetikum, Genetic Counseling and Diagnostics, Genetikum Neu-Ulm, Neu-Ulm, Germany
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Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha, Qatar
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Tartu University Hospital · University of Tartu
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Department of Clinical Genetics, United Laboratories Tartu University Hospital, Tartu, Estonia
Institute of Clinical Medicine, University of Tartu, Tartu, Estonia
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Tartu University Hospital · University of Tartu
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Department of Clinical Genetics, United Laboratories Tartu University Hospital, Tartu, Estonia
Institute of Clinical Medicine, University of Tartu, Tartu, Estonia
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Center of Medical Genetics and Primary Health Care
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Center of Medical Genetics and Primary Health Care, Yerevan, Armenia
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Cytogenetics Laboratory, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy
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Karolinska University Hospital · Karolinska Institutet
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Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
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Karolinska University Hospital · Karolinska Institutet
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Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
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Sahlgrenska University Hospital
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Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden
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Karolinska University Hospital · Science for Life Laboratory · Karolinska Institutet
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Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
Science for Life Laboratory, Karolinska Institutet Science Park, Solna, Sweden
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Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
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Laboratorio de Citogenética Clínica - Centro de Genética Médica, Instituto Nacional Fernandes Figueira - Fiocruz, Rio de Janeiro, Brazil
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University of British Columbia
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Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC Canada
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Department of Medical Genetics, Canakkale 18 March University Medical Faculty, Canakkale 18 March University, Research Hospital, Medical Genetic Lab, Canakkale, Turkey
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FRIGE Institute of Human Genetics, Ahmedabad, India
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Bambino Gesù Children's Hospital
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Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
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Oslo University Hospital · University of Oslo
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Department of Medical Genetics, Oslo University Hospital and University of Oslo, Olso, Norway
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Oslo University Hospital · University of Oslo
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Department of Medical Genetics, Oslo University Hospital and University of Oslo, Olso, Norway
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Oslo University Hospital · University of Oslo
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Division of Pediatric and Adolescent Medicine, Oslo University Hospital and University of Oslo, Olso, Norway
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University of Maribor · University Clinical Centre Maribor
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Laboratory of Medical Genetics, University Medical Centre Maribor, Maribor, Slovenia
Medical Faculty University of Maribor, Maribor, Slovenia
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Prenatal-Medicine Munich, Friedenheimer Brücke, München, Germany
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Universidade Estadual Paulista (Unesp)
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Chemical and Biological Sciences Department, São Paulo State University (UNESP), São Paulo, Brazil
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Universidade Estadual Paulista (Unesp)
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Chemical and Biological Sciences Department, São Paulo State University (UNESP), São Paulo, Brazil
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Servicio de Genética, Hospital Universitario de Navarra, SNS-Osasunbidea, C/ Irunlarrea 4, Pamplona, Navarra, Spain
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Servicio de Genética, Hospital Universitario de Navarra, SNS-Osasunbidea, C/ Irunlarrea 4, Pamplona, Navarra, Spain
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Medical University of Varna · University Hospital St. Marina
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Department of Medical Genetics, Medical University of Varna, Bulgaria
Laboratory of Medical Genetics, St Marina University Hospital, Varna, Bulgaria
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Diagnostic and Research Institute for Human Genetics, Medical University of Graz, Graz, Austria
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Consejo Nacional de Investigaciones Científicas y Técnicas · Hospital General de Niños Ricardo Gutierrez
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Centro de Investigaciones Endocrinológicas “Dr César Bergadá”, CONICET. FEI, Hospital de Niños “Ricardo Gutiérrez”, Buenos Aires, Argentina
Centro de Investigaciones Endocrinológicas "Dr César Bergadá", CONICET. FEI, Hospital de Niños "Ricardo Gutiérrez", Buenos Aires, Argentina
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Universidade Estadual de Campinas (UNICAMP)
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Department of Medical Genetics, State University of Campinas (Unicamp), Campinas, São Paulo, Brazil
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University of British Columbia
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Department of Medical Genetics, The University of British Columbia, Vancouver, BC, Canada
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Hangzhou Women’s Hospital · Zhejiang University
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Department of Cell Biology and Medical Genetics, School of Medicine, Zhejiang University, Zhejiang, China
Prenatal Diagnosis Center, Hangzhou Women’s Hospital, Hangzhou, China
Prenatal Diagnosis Center, Hangzhou Women's Hospital, Hangzhou, China
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Charles University · University Hospital in Motol
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Department of Biology and Medical Genetics, Charles University Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
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Charles University · University Hospital in Motol
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Department of Biology and Medical Genetics, Charles University Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
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Charles University · University Hospital in Motol
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Department of Biology and Medical Genetics, Charles University Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
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Charles University · University Hospital in Motol
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Department of Biology and Medical Genetics, Charles University Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
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Aarhus University · Aarhus University Hospital
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Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark
Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
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Copenhagen University Hospital · Rigshospitalet
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Department of Clinical Genetics, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
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University of Southern Denmark · Filadelfia
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Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Centre, Filadelfia, Dianalund and University of Southern Denmark, Odense, Denmark
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University of Copenhagen · Copenhagen University Hospital · Kennedy Center
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Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Copenhagen, Denmark
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Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
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University of Southern Denmark · Odense University Hospital
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Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
Department of Clinical Research, University of Southern Denmark, Odense, Denmark
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Copenhagen University Hospital · Rigshospitalet · Kennedy Center
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Department of Clinical Genetics, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Copenhagen, Denmark
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Department of Clinical Genetics, Vejle Hospital, Copenhagen, Denmark
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Centre de Génétique Humaine, Centre Hospitalier Régional Universitaire, Université de Franche-Comté, Besançon, France
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Centre Hospitalier Universitaire de Clermont-Ferrand
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CHRU Clermont-Ferrand, Clermont, France
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Centre Hospitalier Universitaire de Rennes
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Service de Cytogénétique et Biologie Cellulaire, CHU Rennes, Rennes, France
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Institute of Medical Genetics and Human Genetics, Augustenburger Platz, Berlin, Germany
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General University Hospital of Patras
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Lab of Medical Genetics, University General Hospital of Patras, Patras, Greece
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Affiliation as printed
Department of Medical Genetics, University of Pécs Medical School, Pecs, Hungary
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Affiliation as printed
Department of Medical Genetics, University of Pécs Medical School, Pecs, Hungary
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Centre for DNA Fingerprinting and Diagnostics
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Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, India
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Centre for DNA Fingerprinting and Diagnostics
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Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, India
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All India Institute of Medical Sciences
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Department of Pediatrics, Division of Genetics, All India Institute of Medical Sciences, New Delhi, India
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Affiliation as printed
Medical Genetics Unit, A.O.R.N. “San Pio” - P.O. “G. Rummo”, Benevento, Italy
Medical Genetics Unit, A.O.R.N. "San Pio" - P.O. "G. Rummo", Benevento, Italy
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Department of Molecular Medicine, University of Pavia, Pavia, Italy
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Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway
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Oslo University Hospital · University of Oslo
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Department of Medical Genetics, Oslo University Hospital and University of Oslo, Olso, Norway
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National Institute for Biotechnology and Genetic Engineering
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Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan
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Medical University of Białystok
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Department of Clinical Genetics, Medical University of Bialystok, Bialystok, Poland
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Medical University of Białystok
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Department of Clinical Genetics, Medical University of Bialystok, Bialystok, Poland
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Centro de Investigação em Meio Ambiente Genética e Oncobiologia · University of Coimbra
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Cytogenetics and Genomics Laboratory, Clinical Academic Center of Coimbra, iCBR/CIMAGO-CIBB, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
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Centro de Investigação em Meio Ambiente Genética e Oncobiologia · University of Coimbra
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Cytogenetics and Genomics Laboratory, Clinical Academic Center of Coimbra, iCBR/CIMAGO-CIBB, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
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Affiliation as printed
HM Hospitales, Madrid, Spain
Technical Director of the Laboratory of Genetics and Molecular Biology, AbaCid laboratory, Madrid, Spain