Comprehensive reanalysis for CNVs in ES data from unsolved rare disease cases results in new diagnoses
npj Genomic Medicine, vol. 9, pp. 49
Abstract
We report the results of a comprehensive copy number variant (CNV) reanalysis of 9171 exome sequencing datasets from 5757 families affected by a rare disease (RD). The data reanalysed was extremely heterogeneous, having been generated using 28 different enrichment kits by 42 different research groups across Europe partnering in the Solve-RD project. Each research group had previously undertaken their own analysis of the data but failed to identify disease-causing variants. We applied three CNV calling algorithms to maximise sensitivity, and rare CNVs overlapping genes of interest, provided by four partner European Reference Networks, were taken forward for interpretation by clinical experts. This reanalysis has resulted in a molecular diagnosis being provided to 51 families in this sample, with ClinCNV performing the best of the three algorithms. We also identified partially explanatory pathogenic CNVs in a further 34 individuals. This work illustrates the value of reanalysing ES cold cases for CNVs.
Authors 33
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German M. Demidov corresponding
Affiliation as printed
Institute for Bioinformatics and Medical Informatics (IBMI), University of Tübingen, Tübingen, Germany. German.Demidov@med.uni-tuebingen.de
Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany. German.Demidov@med.uni-tuebingen.de
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Maastricht University Medical Centre · Radboud University Medical Center · Maastricht University
Affiliation as printed
Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
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Universidade do Porto · i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto
Affiliation as printed
Faculty of Medicine, University of Porto, Porto, Portugal
IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
i3S - Instituto de Investigação e Inovação em Saúde, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal
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Radboud University Nijmegen · Erasmus MC · Radboud University Medical Center · Donders Institute for Brain, Cognition and Behaviour
Affiliation as printed
Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands
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Affiliation as printed
Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
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University of Antwerp · Institute Born-Bunge
Affiliation as printed
Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
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Centro Nacional de Análisis Genómico · Universitat de Barcelona
Affiliation as printed
Centro Nacional de Análisis Genómico (CNAG), C/Baldiri Reixac 4, 08028, Barcelona, Spain
Universitat de Barcelona (UB), Barcelona, Spain
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Italian Institute of Technology · Telethon Institute Of Genetics And Medicine
Affiliation as printed
Center for Human Technologies, Italian Institute of Technology (IIT), Genova, Italy
Telethon Institute for Genetics and Medicine, 80078, Pozzuoli (Napoli), Italy
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Affiliation as printed
Department of Medical Biotechnologies, Med Biotech Hub and Competence Center, University of Siena, 53100, Siena, Italy
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Centro Nacional de Análisis Genómico · Universitat de Barcelona
Affiliation as printed
Centro Nacional de Análisis Genómico (CNAG), C/Baldiri Reixac 4, 08028, Barcelona, Spain
Universitat de Barcelona (UB), Barcelona, Spain
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Vilnius University · Radboud University Medical Center
Affiliation as printed
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
Institute of Data Science and Digital Technologies, Vilnius University, Vilnius, Lithuania
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Centro Nacional de Análisis Genómico · Universitat de Barcelona
Affiliation as printed
Centro Nacional de Análisis Genómico (CNAG), C/Baldiri Reixac 4, 08028, Barcelona, Spain
Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona (UB), Barcelona, Spain
Universitat de Barcelona (UB), Barcelona, Spain
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Radboud University Medical Center
Affiliation as printed
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
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Radboud University Nijmegen · Radboud University Medical Center · Radboud Institute for Molecular Life Sciences
Affiliation as printed
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands
Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
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Affiliation as printed
Institute for Bioinformatics and Medical Informatics (IBMI), University of Tübingen, Tübingen, Germany
Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
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Radboud University Medical Center
Affiliation as printed
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands
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Affiliation as printed
Institute of Neurogenetics, University of Lübeck, Ratzeburger Allee 160, 23562, Lübeck, Germany
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Universidade do Porto · i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto
Affiliation as printed
Faculty of Medicine, University of Porto, Porto, Portugal
IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
i3S - Instituto de Investigação e Inovação em Saúde, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal
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Newcastle upon Tyne Hospitals NHS Foundation Trust · Newcastle University
Affiliation as printed
John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
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Radboud University Nijmegen · Radboud University Medical Center · Donders Institute for Brain, Cognition and Behaviour
Affiliation as printed
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands
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Heidelberg University · Hertie Institute for Clinical Brain Research · University of Tübingen
Affiliation as printed
Department of Neurodegeneration, Hertie Institute for Clinical Brain Research (HIH), University of Tübingen, Tübingen, Germany
Division of Neurodegenerative Diseases and Movement Disorders, Department of Neurology, University of Heidelberg, Heidelberg, Germany
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German Center for Neurodegenerative Diseases · Hertie Institute for Clinical Brain Research · University of Tübingen
Affiliation as printed
Department of Neurodegeneration, Hertie Institute for Clinical Brain Research (HIH), University of Tübingen, Tübingen, Germany
German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
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Hertie Institute for Clinical Brain Research · University of Tübingen
Affiliation as printed
Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research (HIH), University of Tübingen, Tübingen, Germany
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Radboud University Medical Center · Radboud Institute for Molecular Life Sciences
Affiliation as printed
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
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Radboud University Nijmegen · Radboud University Medical Center · Donders Institute for Brain, Cognition and Behaviour
Affiliation as printed
Department of Neurology, Radboud University Medical Center, Nijmegen, The Netherlands
Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands
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Affiliation as printed
Department of Genetics and Genome Biology, University of Leicester, Leicester, UK
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Newcastle upon Tyne Hospitals NHS Foundation Trust · Newcastle University
Affiliation as printed
John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
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Newcastle upon Tyne Hospitals NHS Foundation Trust · Newcastle upon Tyne Hospital · Newcastle University
Affiliation as printed
Primary Immunodeficiency Group, Translational and Clinical Research Institute, Newcastle University and Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
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University of Manchester · St Mary's Hospital · Health Innovation Manchester
Affiliation as printed
Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9WL, UK
Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester University Hospitals NHS Foundation Trust, Health Innovation Manchester, Manchester, M13 9WL, UK
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Inserm · Université de Bourgogne · Centre de recherche Translationnelle en Médecine moléculaire
Affiliation as printed
Inserm - University of Burgundy-Franche Comté, UMR1231 GAD, Dijon, France
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Inserm · Université de Bourgogne · Centre de recherche Translationnelle en Médecine moléculaire
Affiliation as printed
Inserm - University of Burgundy-Franche Comté, UMR1231 GAD, Dijon, France
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Centro Nacional de Análisis Genómico · Universitat de Barcelona
Affiliation as printed
Centro Nacional de Análisis Genómico (CNAG), C/Baldiri Reixac 4, 08028, Barcelona, Spain
Universitat de Barcelona (UB), Barcelona, Spain
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Universitat Pompeu Fabra · Centro Nacional de Análisis Genómico
Affiliation as printed
Centro Nacional de Análisis Genómico (CNAG), C/Baldiri Reixac 4, 08028, Barcelona, Spain
Universitat Pompeu Fabra (UPF), Barcelona, Spain