PMEPA1 protein, human; Membrane Proteins; Humans; Bayes Theorem; Genotype; Phenotype; Rare Diseases/genetics; Genome-Wide Association Study/methods; Genome-Wide Association Study; Rare Diseases; Biochemistry, Genetics and Molecular Biology (all); General Biochemistry, Genetics and Molecular Biology; General Medicine
Abstract :
[en] The genetic etiologies of more than half of rare diseases remain unknown. Standardized genome sequencing and phenotyping of large patient cohorts provide an opportunity for discovering the unknown etiologies, but this depends on efficient and powerful analytical methods. We built a compact database, the 'Rareservoir', containing the rare variant genotypes and phenotypes of 77,539 participants sequenced by the 100,000 Genomes Project. We then used the Bayesian genetic association method BeviMed to infer associations between genes and each of 269 rare disease classes assigned by clinicians to the participants. We identified 241 known and 19 previously unidentified associations. We validated associations with ERG, PMEPA1 and GPR156 by searching for pedigrees in other cohorts and using bioinformatic and experimental approaches. We provide evidence that (1) loss-of-function variants in the Erythroblast Transformation Specific (ETS)-family transcription factor encoding gene ERG lead to primary lymphoedema, (2) truncating variants in the last exon of transforming growth factor-β regulator PMEPA1 result in Loeys-Dietz syndrome and (3) loss-of-function variants in GPR156 give rise to recessive congenital hearing impairment. The Rareservoir provides a lightweight, flexible and portable system for synthesizing the genetic and phenotypic data required to study rare disease cohorts with tens of thousands of participants.
Disciplines :
Genetics & genetic processes
Author, co-author :
Greene, Daniel; Department of Medicine, University of Cambridge, Cambridge, UK ; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Genomics England Research Consortium
Pirri, Daniela; National Heart and Lung Institute, Imperial College London, London, UK
Frudd, Karen; National Heart and Lung Institute, Imperial College London, London, UK ; University College London Institute of Ophthalmology, University College London, London, UK
Sackey, Ege; Molecular and Clinical Sciences Institute, St. George's University of London, London, UK
Al-Owain, Mohammed; Department of Medical Genomics, Centre for Genomic Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
Giese, Arnaud P J ; Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD, USA
Ramzan, Khushnooda; Department of Clinical Genomics, Centre for Genomic Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
Riaz, Sehar; Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD, USA ; Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD, USA
Yamanaka, Itaru ; Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center, Osaka, Japan
Boeckx, Nele; Center for Medical Genetics, Antwerp University Hospital/University of Antwerp, Antwerp, Belgium
Thys, Chantal; Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium
Gelb, Bruce D ; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA ; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA ; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Brennan, Paul; Northern Genetics Service, Newcastle upon Tyne Hospitals National Health Service Trust International Centre for Life, Newcastle upon Tyne, UK
Hartill, Verity; Department of Clinical Genetics, Chapel Allerton Hospital, Leeds Teaching Hospitals National Health Service Trust, Leeds, UK ; Leeds Institute of Medical Research, University of Leeds, Leeds, UK
Harvengt, Julie ; Centre Hospitalier Universitaire de Liège - CHU > > Service de génétique
Kosho, Tomoki ; Department of Medical Genetics, Shinshu University School of Medicine, Nagano, Japan ; Center for Medical Genetics, Shinshu University Hospital, Nagano, Japan
Mansour, Sahar; Molecular and Clinical Sciences Institute, St. George's University of London, London, UK ; South West Thames Regional Genetics Service, St. George's University Hospitals National Health Service Foundation Trust, London, UK
Masuno, Mitsuo; Department of Medical Genetics, Kawasaki Medical School Hospital, Okayama, Japan
Ohata, Takako; Okinawa Chubu Hospital, Okinawa, Japan
Stewart, Helen; Oxford University Hospitals National Health Service Foundation Trust, Oxford, UK
Taibah, Khalid; Ear Nose and Throat Medical Centre, Riyadh, Saudi Arabia
Turner, Claire L S; Peninsula Clinical Genetics Service, Royal Devon & Exeter Hospital, Exeter, UK
Imtiaz, Faiqa; Department of Clinical Genomics, Centre for Genomic Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
Riazuddin, Saima ; Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD, USA ; Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD, USA
Morisaki, Takayuki; Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center, Osaka, Japan ; Division of Molecular Pathology and Department of Internal Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Ostergaard, Pia ; Molecular and Clinical Sciences Institute, St. George's University of London, London, UK
Loeys, Bart L ; Center for Medical Genetics, Antwerp University Hospital/University of Antwerp, Antwerp, Belgium ; Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
Morisaki, Hiroko; Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center, Osaka, Japan ; Department of Medical Genetics, Sakakibara Heart Institute, Tokyo, Japan
Ahmed, Zubair M ; Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD, USA ; Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD, USA
Birdsey, Graeme M ; National Heart and Lung Institute, Imperial College London, London, UK
Freson, Kathleen; Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium
Mumford, Andrew; School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK ; South West National Health Service Genomic Medicine Service Alliance, Bristol, UK
Turro, Ernest ; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. ernest.turro@mssm.edu ; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. ernest.turro@mssm.edu ; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK. ernest.turro@mssm.edu ; Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. ernest.turro@mssm.edu
This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and National Health Service (NHS) England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. GS was performed by Illumina at Illumina Laboratory Services and was overseen by Genomics England. We thank all NHS clinicians who have contributed clinical phenotype data to the 100,000 Genomes Rare Diseases Programme and all staff at Genomics England who have contributed to the sequencing, maintenance of the research environment and assembly of the standard bioinformatic files that were required for our analyses. We thank the participants of the rare diseases program who made this research possible. We are grateful to V. Keeley for providing access to paternal DNA (ERG), F. Elmslie for inviting a patient to the clinic (ERG) and T. Jaworek for technical assistance (GPR156). D.G. was supported by the Cambridge British Heart Foundation (BHF) Centre of Research Excellence (RE/18/1/34212) and the Wellcome Collaborative (219506/Z/19/Z). V.H. was supported by an Medical Research Council (MRC)/National Institute for Health and Care Research Clinical Academic Research Partnership (MR/V037617/1). G.M.B. and K. Frudd were funded by BHF (PG/17/33/32990). G.M.B. and D.P. were funded by BHF (PG/20/16/35047). E.S. was supported by the Swiss Federal National Fund for Scientific Research (CRSII5_177191/1). S.M. and P.O. were supported by the MRC (MR/P011543/1) and BHF (RG/17/7/33217). K. Freson was supported by Katholieke Universiteit (KU) Leuven Special Research Fund (BOF) (C14/19/096) and Research Foundation – Flanders (G072921N). Work at the University of Maryland, Baltimore was supported by the National Institute on Deafness and Other Communication Disorders/National Institutes of Health (R01DC016295 to Z.M.A.). M.A.-O., F.I. and K.R. were supported by the King Salman Center for Disability Research (85722). E.T. was supported by the Mindich Child Health and Development Institute, the Charles Bronfman Institute for Personalized Medicine and the Lowy Foundation USA.This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and National Health Service (NHS) England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. GS was performed by Illumina at Illumina Laboratory Services and was overseen by Genomics England. We thank all NHS clinicians who have contributed clinical phenotype data to the 100,000 Genomes Rare Diseases Programme and all staff at Genomics England who have contributed to the sequencing, maintenance of the research environment and assembly of the standard bioinformatic files that were required for our analyses. We thank the participants of the rare diseases program who made this research possible. We are grateful to V. Keeley for providing access to paternal DNA (ERG), F. Elmslie for inviting a patient to the clinic (ERG) and T. Jaworek for technical assistance (GPR156). D.G. was supported by the Cambridge British Heart Foundation (BHF) Centre of Research Excellence (RE/18/1/34212) and the Wellcome Collaborative (219506/Z/19/Z). V.H. was supported by an Medical Research Council (MRC)/National Institute for Health and Care Research Clinical Academic Research Partnership (MR/V037617/1). G.M.B. and K. Frudd were funded by BHF (PG/17/33/32990). G.M.B. and D.P. were funded by BHF (PG/20/16/35047). E.S. was supported by the Swiss Federal National Fund for Scientific Research (CRSII5_177191/1). S.M. and P.O. were supported by the MRC (MR/P011543/1) and BHF (RG/17/7/33217). K. Freson was supported by Katholieke Universiteit (KU) Leuven Special Research Fund (BOF) (C14/19/096) and Research Foundation – Flanders (G072921N). Work at the University of Maryland, Baltimore was supported by the National Institute on Deafness and Other Communication Disorders/National Institutes of Health (R01DC016295 to Z.M.A.). M.A.-O., F.I. and K.R. were supported by the King Salman Center for Disability Research (85722). E.T. was supported by the Mindich Child Health and Development Institute, the Charles Bronfman Institute for Personalized Medicine and the Lowy Foundation USA.
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