1. A loss-of-function IFNAR1 allele in Polynesia underlies severe viral diseases in homozygotes
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Paul Bastard, Kuang-Chih Hsiao, Qian Zhang, Jeremy Choin, Emma Best, Jie Chen, Adrian Gervais, Lucy Bizien, Marie Materna, Christine Harmant, Maguelonne Roux, Nicola L. Hawley, Daniel E. Weeks, Stephen T. McGarvey, Karla Sandoval, Carmina Barberena-Jonas, Consuelo D. Quinto-Cortés, Erika Hagelberg, Alexander J. Mentzer, Kathryn Robson, Boubacar Coulibaly, Yoann Seeleuthner, Benedetta Bigio, Zhi Li, Gilles Uzé, Sandra Pellegrini, Lazaro Lorenzo, Zineb Sbihi, Sylvain Latour, Marianne Besnard, Tiphaine Adam de Beaumais, Evelyne Jacqz Aigrain, Vivien Béziat, Ranjan Deka, Litara Esera Tulifau, Satupa‘itea Viali, Muagututi‘a Sefuiva Reupena, Take Naseri, Peter McNaughton, Vanessa Sarkozy, Jane Peake, Annaliesse Blincoe, Sarah Primhak, Simon Stables, Kate Gibson, See-Tarn Woon, Kylie Marie Drake, Adrian V.S. Hill, Cheng-Yee Chan, Richard King, Rohan Ameratunga, Iotefa Teiti, Maite Aubry, Van-Mai Cao-Lormeau, Stuart G. Tangye, Shen-Ying Zhang, Emmanuelle Jouanguy, Paul Gray, Laurent Abel, Andrés Moreno-Estrada, Ryan L. Minster, Lluis Quintana-Murci, Andrew C. Wood, Jean-Laurent Casanova, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Rockefeller University [New York], Human genetics of infectious diseases: Complex predisposition (Equipe Inserm U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Département de Pédiatrie et maladies infectieuses [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Howard Hughes Medical Institute (HHMI), University of Auckland [Auckland], Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Collège de France - Chaire Génomique humaine et évolution, Collège de France (CdF (institution)), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Langebio (CINVESTAV), University of New South Wales [Sydney] (UNSW), Sydney Children's hospital, Garvan Institute of medical research, UNSW Faculty of Medicine [Sydney], Institut Louis Malardé [Papeete] (ILM), Institut de Recherche pour le Développement (IRD), Auckland City Hospital, Canterbury Health Laboratories, University of Oxford, University of Queensland [Brisbane], Brown University, Ministry of Health [Samoa], Tupua Tamasese Meaole Hospital (TTM), University of Cincinnati (UC), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Cité (UPCité), Institut Gustave Roussy (IGR), Centre Hospitalier de Polynésie Française, Signalisation des Cytokines - Cytokine Signaling, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), University of Oslo (UiO), National Laboratory of Genomics for Biodiversity (LANGEBIO), Centro de Investigacion y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), Yale University [New Haven], Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Shanghai Jiaotong University, Murdoch Children's Research Institute (MCRI), The laboratory of V.-M. Cao-Lormeau is supported by MATAEA grant no. 03557/MED/REC_29/05/2019 (Délégation à la recherche de la Polynésie française). The Laboratory of Human Evolutionary Genetics is supported by Institut Pasteur, Collège de France, the Centre national de la recherche scientifique, Fondation Allianz-Institut de France, the French Government’s Investissement d’Avenir program, Laboratoires d’Excellence 'Integrative Biology of Emerging Infectious Diseases' (ANR-10-LABX-62-IBEID) and 'Milieu Intérieur' (ANR-10-LABX-69-01), Fondation de France (grant no. 00106080), and Fondation pour la Recherche Médicale (Equipe FRM DEQ20180339214). The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH, R01AI088364 and R01AI163029), the National Center for Advancing Translational Sciences, the NIH Clinical and Translational Science Award program (UL1 TR001866), a Fast Grant from Emergent Ventures, Mercatus Center at George Mason University, the Yale Center for Mendelian Genomics, and the Genome Sequencing Program Coordinating Center funded by the National Human Genome Research Institute (UM1HG006504 and U24HG008956), the Yale High-Performance Computing Center (S10OD018521), the Fisher Center for Alzheimer’s Research Foundation, the Meyer Foundation, the French National Research Agency (ANR) under the 'Investments for the Future' program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM, EQU201903007798), the FRM and ANR GENCOVID project, the ANRS-COV05, ANR GENVIR (ANR-20-CE93-003), and ANR AABIFNCOV (ANR-20-CO11-0001) projects, the European Union’s Horizon 2020 research and innovation program under grant agreement 824110 (EASI-genomics), the Square Foundation, Grandir - Fonds de solidarité pour l’enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, INSERM, the French Ministry of Higher Education, Research, and Innovation (MESRI-COVID-19), and the University of Paris. P. Bastard was supported by the FRM (EA20170638020) and by the MD-PhD program of the Imagine Institute (with the support of Fondation Bettencourt-Schueller). The National Laboratory of Genomics for Biodiversity (LANGEBIO-CINVESTAV) in Mexico is supported by Consejo Nacional de Ciencia y Technologia (grant number FONCICYT/50/2016), The Newton Fund through the Medical Research Council (grant number MR/N028937/1), and the International Center for Genetic Engineering and Biotechnology grant number CRP/MEX20-01, awarded to A. Moreno-Estrada. S.G. Tangye is supported by a Leadership 3 Investigator Grant awarded by the National Health and Medical Research Council of Australia (1176665) and the Jeffrey Modell Foundation. Clinical Immunogenomics Research Consortium Australasia investigators (K.-C. Hsiao, P. McNaughton, A. Blincoe, J. Peake, S.G. Tangye, and P. Gray) are supported by the John Brown Cook Foundation. This work was supported by the National Institutes of Health grants R01-HL093093 (S.T. McGarvey) and R01-HL133040 (R.L. Minster). Molecular data for the Trans-Omics in Precision Medicine (TOPMed) program were provided by the National Heart, Lung, and Blood Institute (NHLBI). Genome sequencing for the Soifua Manuia study, labeled 'NHLBI TOPMed: Genome-wide Association Study of Adiposity in Samoans' (phs000972.v4.p1) in the dbGaP, was performed at the Northwest Genomics Center (HHSN268201100037C) and the New York Genome Center (HHSN268201500016C). Core support, including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering, was provided by the TOPMed Informatics Research Center (3R01-HL117626-02S1, contract HHSN268201800002I). Core support, including phenotype harmonization, data management, sample-identity QC, and general program coordination, was also provided by the TOPMed Data Coordinating Center (R01-HL120393, U01-HL120393, contract HHSN268201800001I). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. This research was funded in whole or in part by the French National Research Agency (ANR)., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-20-COVI-0003,GENCOVID,Identification des défauts monogéniques de l'immunité responsables des formes sévères de COVID-19 chez les patients précédemment en bonne santé(2020), ANR-20-CE93-0003,GENVIR,Analyse multi-omique de l'immunité anti-virale: de l'identification des circuits biologiques pertinents à la découverte de défauts monogéniques héréditaires de l'immunité chez les patients avec infections virales sévères(2020), ANR-20-CO11-0001,AABIFNCOV,Bases génétiques et immunologiques des auto-anticorps contre les interférons de type I prédisposant aux formes sévères de COVID-19.(2020), European Project: 824110,H2020-INFRAIA-2018-1,EASI-Genomics(2019), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), Institut Pasteur [Paris]-Université Paris Cité (UPC), University of Oxford [Oxford], Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Institute for Regenerative Medicine and Biotherapy [Montpellier], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Université Paris Cité (UPC), Garvan Institute of Medical Research [Sydney, Australia], and Chaire Génomique humaine et évolution
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[SDV.GEN]Life Sciences [q-bio]/Genetics ,Infectious disease and host defense ,Homozygote ,Immunology ,Innate immunity and inflammation ,Receptor, Interferon alpha-beta ,Polynesia ,Virus Diseases ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Humans ,Immunology and Allergy ,Immunodeficiency ,Child ,Alleles ,Human disease genetics - Abstract
International audience; Globally, autosomal recessive IFNAR1 deficiency is a rare inborn error of immunity underlying susceptibility to live attenuated vaccine and wild-type viruses. We report seven children from five unrelated kindreds of western Polynesian ancestry who suffered from severe viral diseases. All the patients are homozygous for the same nonsense IFNAR1 variant (p.Glu386*). This allele encodes a truncated protein that is absent from the cell surface and is loss-of-function. The fibroblasts of the patients do not respond to type I IFNs (IFN-α2, IFN-ω, or IFN-β). Remarkably, this IFNAR1 variant has a minor allele frequency >1% in Samoa and is also observed in the Cook, Society, Marquesas, and Austral islands, as well as Fiji, whereas it is extremely rare or absent in the other populations tested, including those of the Pacific region. Inherited IFNAR1 deficiency should be considered in individuals of Polynesian ancestry with severe viral illnesses.
- Published
- 2022
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