The RD-Connect Genome-Phenome Analysis Platform: Accelerating diagnosis, research, and gene discovery for rare diseases

Steven Laurie¹, Davide Piscia¹, Leslie Matalonga¹, Alberto Corvó¹, Marcos Fernández-Callejo¹, Carles Garcia-Linares^{1

2}, Carles Hernandez-Ferrer¹, Cristina Luengo¹, Inés Martínez¹, Anastasios Papakonstantinou¹, Daniel Picó-Amador¹, Joan Protasio¹, Rachel Thompson³, Raul Tonda¹, Mònica Bayés¹, Gemma Bullich¹, Jordi Camps-Puchadas¹, Ida Paramonov¹, Jean-Rémi Trotta¹, Angel Alonso⁴, Marcella Attimonelli⁵, Christophe Béroud^{6

7}, Virginie Bros-Facer⁸, Orion J Buske⁹, Andrés Cañada-Pallarés, José M Fernández¹⁰, Mats G Hansson¹¹, Rita Horvath¹², Julius O B Jacobsen¹³, Rajaram Kaliyaperumal¹⁴, Séverine Lair-Préterre¹⁵, Luana Licata^{16

17}, Pedro Lopes¹⁸, Estrella López-Martín¹⁹, Deborah Mascalzoni^{20

21}, Lucia Monaco²², Luis A Pérez-Jurado^{23

24

25}, Manuel Posada de la Paz¹⁹, Jordi Rambla^{26

27}, Ana Rath²⁸, Olaf Riess²⁹, Peter N Robinson³⁰, David Salgado^{6

31}, Damian Smedley¹³, Dylan Spalding^{2

32}, Peter A C 't Hoen³³, Ana Töpf³⁴, Irina Zaharieva³⁵, Holm Graessner^{36

37}, Ivo G Gut^{1

27}, Hanns Lochmüller^{1

3

38

39

40}, Sergi Beltran^{1

27

41}

Affiliations

¹ CNAG-CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
² European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, UK.
³ Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
⁴ Genomic Medicine Unit, Navarrabiomed-Universidad Pública de Navarra (UPNA)-Hospital Universitario de Navarra (HUN), IdiSNA, Pamplona, Navarra, Spain.
⁵ Department of Biosciences, Biotechnology and Biopharmaceutics, University of A. Moro, Bari, Italy.
⁶ INSERM, Marseille Medical Genetics, Aix Marseille University, Marseille, France.
⁷ Département de Génétique Médicale, APHM, Hôpital d'Enfants de la Timone, Marseille, France.
⁸ EURORDIS-Rare Diseases Europe.
⁹ Phenotips, Toronto, Ontario, Canada.
¹⁰ Barcelona Supercomputing Center, Spain.
¹¹ Centre for Research Ethics & Bioethics, Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
¹² Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
¹³ Queen Mary University of London, William Harvey Research Institute, London, UK.
¹⁴ Leiden University Medical Center, Leiden, The Netherlands.
¹⁵ CHU Rouen, Rouen, France.
¹⁶ Department of Biology, University of Rome Tor Vergata, Rome, Italy.
¹⁷ Fondazione Human Technopole, Milan, Italy.
¹⁸ IEETA, Aveiro, Portugal.
¹⁹ Institute of Rare Diseases Research, Spanish Undiagnosed Rare Diseases Cases Program (SpainUDP) & Undiagnosed Diseases Network International (UDNI), Instituto de Salud Carlos III, Madrid, Spain.
²⁰ CRB-Center for Ethics and Bioethics, Uppsala University, Sweden.
²¹ Eurac Research Bolzano, Italy.
²² Fondazione Telethon, Milan, Italy.
²³ Genetics Unit, Departament de Medicina i Ciències de la Vida, Universitat Pompeu Fabra, Barcelona, Spain.
²⁴ Genetics Service, Hospital del Mar & Hospital del Mar Research Institute (IMIM), Barcelona, Spain.
²⁵ Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.
²⁶ Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.
²⁷ Universitat Pompeu Fabra (UPF), Barcelona, Spain.
²⁸ INSERM, US-14 Orphanet, Paris, France.
²⁹ Institute for Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
³⁰ The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
³¹ CNRS, Institut Français de Bioinformatique, IFB-core, Evry, France.
³² CSC-IT Center for Science, Life Science Center, Espoo, Finland.
³³ Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
³⁴ John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, UK.
³⁵ UCL Great Ormond Street Institute of Child Health, Dubowitz Neuromuscular Unit, London, UK.
³⁶ Institute for Medical Genetics and Applied Genomics, Centre for Rare Diseases, University Hospital Tübingen, Tübingen, Germany.
³⁷ European Reference Network for Rare Neurological Diseases.
³⁸ Division of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa, Canada.
³⁹ Brain and Mind Research Institute, University of Ottawa, Ottawa, Canada.
⁴⁰ Department of Neuropediatrics and Muscle Disorders, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany.
⁴¹ Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona (UB), Barcelona, Spain.

PMID: 35178824
PMCID: PMC9324157
DOI: 10.1002/humu.24353

The RD-Connect Genome-Phenome Analysis Platform: Accelerating diagnosis, research, and gene discovery for rare diseases

Steven Laurie et al. Hum Mutat. 2022 Jun.

. 2022 Jun;43(6):717-733.

doi: 10.1002/humu.24353.

Authors

Affiliations

¹ CNAG-CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
² European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, UK.
³ Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
⁴ Genomic Medicine Unit, Navarrabiomed-Universidad Pública de Navarra (UPNA)-Hospital Universitario de Navarra (HUN), IdiSNA, Pamplona, Navarra, Spain.
⁵ Department of Biosciences, Biotechnology and Biopharmaceutics, University of A. Moro, Bari, Italy.
⁶ INSERM, Marseille Medical Genetics, Aix Marseille University, Marseille, France.
⁷ Département de Génétique Médicale, APHM, Hôpital d'Enfants de la Timone, Marseille, France.
⁸ EURORDIS-Rare Diseases Europe.
⁹ Phenotips, Toronto, Ontario, Canada.
¹⁰ Barcelona Supercomputing Center, Spain.
¹¹ Centre for Research Ethics & Bioethics, Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
¹² Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
¹³ Queen Mary University of London, William Harvey Research Institute, London, UK.
¹⁴ Leiden University Medical Center, Leiden, The Netherlands.
¹⁵ CHU Rouen, Rouen, France.
¹⁶ Department of Biology, University of Rome Tor Vergata, Rome, Italy.
¹⁷ Fondazione Human Technopole, Milan, Italy.
¹⁸ IEETA, Aveiro, Portugal.
¹⁹ Institute of Rare Diseases Research, Spanish Undiagnosed Rare Diseases Cases Program (SpainUDP) & Undiagnosed Diseases Network International (UDNI), Instituto de Salud Carlos III, Madrid, Spain.
²⁰ CRB-Center for Ethics and Bioethics, Uppsala University, Sweden.
²¹ Eurac Research Bolzano, Italy.
²² Fondazione Telethon, Milan, Italy.
²³ Genetics Unit, Departament de Medicina i Ciències de la Vida, Universitat Pompeu Fabra, Barcelona, Spain.
²⁴ Genetics Service, Hospital del Mar & Hospital del Mar Research Institute (IMIM), Barcelona, Spain.
²⁵ Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.
²⁶ Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.
²⁷ Universitat Pompeu Fabra (UPF), Barcelona, Spain.
²⁸ INSERM, US-14 Orphanet, Paris, France.
²⁹ Institute for Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
³⁰ The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
³¹ CNRS, Institut Français de Bioinformatique, IFB-core, Evry, France.
³² CSC-IT Center for Science, Life Science Center, Espoo, Finland.
³³ Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
³⁴ John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, UK.
³⁵ UCL Great Ormond Street Institute of Child Health, Dubowitz Neuromuscular Unit, London, UK.
³⁶ Institute for Medical Genetics and Applied Genomics, Centre for Rare Diseases, University Hospital Tübingen, Tübingen, Germany.
³⁷ European Reference Network for Rare Neurological Diseases.
³⁸ Division of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa, Canada.
³⁹ Brain and Mind Research Institute, University of Ottawa, Ottawa, Canada.
⁴⁰ Department of Neuropediatrics and Muscle Disorders, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany.
⁴¹ Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona (UB), Barcelona, Spain.

PMID: 35178824
PMCID: PMC9324157
DOI: 10.1002/humu.24353

Abstract

Rare disease patients are more likely to receive a rapid molecular diagnosis nowadays thanks to the wide adoption of next-generation sequencing. However, many cases remain undiagnosed even after exome or genome analysis, because the methods used missed the molecular cause in a known gene, or a novel causative gene could not be identified and/or confirmed. To address these challenges, the RD-Connect Genome-Phenome Analysis Platform (GPAP) facilitates the collation, discovery, sharing, and analysis of standardized genome-phenome data within a collaborative environment. Authorized clinicians and researchers submit pseudonymised phenotypic profiles encoded using the Human Phenotype Ontology, and raw genomic data which is processed through a standardized pipeline. After an optional embargo period, the data are shared with other platform users, with the objective that similar cases in the system and queries from peers may help diagnose the case. Additionally, the platform enables bidirectional discovery of similar cases in other databases from the Matchmaker Exchange network. To facilitate genome-phenome analysis and interpretation by clinical researchers, the RD-Connect GPAP provides a powerful user-friendly interface and leverages tens of information sources. As a result, the resource has already helped diagnose hundreds of rare disease patients and discover new disease causing genes.

Keywords: NGS; data sharing; data standardization; diagnostics; genome analysis; patient matchmaking; rare diseases.

PubMed Disclaimer

Conflict of interest statement

Orion Buske is the CEO of PhenoTips. Jules Jacobsen is a consultant to Congenica. All other authors declare no conflict of interest.

Figures

**Figure 1**
Flow of genome‐phenome data in the RD‐Connect Genome‐Phenome Analysis Platform. Clinical scientists submit their data to the RD‐Connect GPAP wherein it is processed through a standard analysis pipeline. The variants identified are returned to the user via a user‐friendly interface where they can undertake filtration and prioritization to diagnose their rare disease cases. This effort is supported by the integration of data from a large variety of external resources, and through live links via APIs to other resources. When an inconclusive but interesting result is found, patient matchmaking may be performed using the Matchmaker Exchange API to query other similar resources around the world

See this image and copyright information in PMC

References

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The RD-Connect Genome-Phenome Analysis Platform: Accelerating diagnosis, research, and gene discovery for rare diseases

Affiliations

The RD-Connect Genome-Phenome Analysis Platform: Accelerating diagnosis, research, and gene discovery for rare diseases

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases

Research Materials

Miscellaneous