A loss-of-function IFNAR1 allele in Polynesia underlies severe viral diseases in homozygotes

Author:

Bastard Paul1234ORCID,Hsiao Kuang-Chih5678ORCID,Zhang Qian123ORCID,Choin Jeremy91011ORCID,Best Emma56ORCID,Chen Jie212ORCID,Gervais Adrian13ORCID,Bizien Lucy13ORCID,Materna Marie13ORCID,Harmant Christine9ORCID,Roux Maguelonne913ORCID,Hawley Nicola L.1415ORCID,Weeks Daniel E.1617ORCID,McGarvey Stephen T.1518ORCID,Sandoval Karla19ORCID,Barberena-Jonas Carmina19ORCID,Quinto-Cortés Consuelo D.19ORCID,Hagelberg Erika20ORCID,Mentzer Alexander J.2122ORCID,Robson Kathryn23ORCID,Coulibaly Boubacar13ORCID,Seeleuthner Yoann1ORCID,Bigio Benedetta2ORCID,Li Zhi924ORCID,Uzé Gilles25ORCID,Pellegrini Sandra24ORCID,Lorenzo Lazaro13ORCID,Sbihi Zineb26ORCID,Latour Sylvain326ORCID,Besnard Marianne27ORCID,Adam de Beaumais Tiphaine2829ORCID,Jacqz Aigrain Evelyne1129ORCID,Béziat Vivien123ORCID,Deka Ranjan30ORCID,Esera Tulifau Litara31ORCID,Viali Satupa‘itea32ORCID,Reupena Muagututi‘a Sefuiva33,Naseri Take1534ORCID,McNaughton Peter835ORCID,Sarkozy Vanessa3637ORCID,Peake Jane835ORCID,Blincoe Annaliesse58ORCID,Primhak Sarah56ORCID,Stables Simon38ORCID,Gibson Kate39ORCID,Woon See-Tarn4041ORCID,Drake Kylie Marie42ORCID,Hill Adrian V.S.2143ORCID,Chan Cheng-Yee44ORCID,King Richard44ORCID,Ameratunga Rohan404145ORCID,Teiti Iotefa46ORCID,Aubry Maite46ORCID,Cao-Lormeau Van-Mai46ORCID,Tangye Stuart G.84748ORCID,Zhang Shen-Ying123ORCID,Jouanguy Emmanuelle123ORCID,Gray Paul83749ORCID,Abel Laurent123ORCID,Moreno-Estrada Andrés19ORCID,Minster Ryan L.16ORCID,Quintana-Murci Lluis910ORCID,Wood Andrew C.541ORCID,Casanova Jean-Laurent123450ORCID

Affiliation:

1. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France 1

2. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 2

3. Paris Cité University, Imagine Institute, Paris, France 3

4. Department of Pediatrics, Necker Hospital for Sick Children, Assistance Publique – Hôpitaux de Paris, Paris, France 4

5. Starship Child Health, Auckland, New Zealand 5

6. Department of Paediatrics: Child and Youth Health, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand 6

7. Murdoch Children’s Research Institute, Melbourne, Australia 7

8. Clinical Immunogenomics Research Consortium Australasia, Sydney, Australia 8

9. Institut Pasteur, Université de Paris, CNRS UMR2000, Human Evolutionary Genetics Unit, Paris, France 9

10. Chair of Human Genomics and Evolution, Collège de France, Paris, France 10

11. Paris Cité University, Paris, France 11

12. Department of Infectious Diseases, Shanghai Sixth Hospital, Shanghai Jiaotong University, Shanghai, China 12

13. Institut Pasteur, Université de Paris, Bioinformatics and Biostatistics Hub, Paris, France 13

14. Department of Chronic Disease Epidemiology, Yale University School of Public Health, New Haven, CT 14

15. International Health Institute, Department of Epidemiology, School of Public Health, Brown University, Providence, RI 15

16. Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA 16

17. Department of Biostatistics, School of Public Health, University of Pittsburgh, Pittsburgh, PA 17

18. Department of Anthropology, Brown University, Providence, RI 18

19. National Laboratory of Genomics for Biodiversity (LANGEBIO) - UGA, CINVESTAV, Irapuato, Guanajuato, Mexico 19

20. Department of Biology, University of Oslo, Oslo, Norway 20

21. Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK 21

22. Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK 22

23. MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK 23

24. Unit of Cytokine Signaling, Pasteur Institute, INSERM U1224, Paris, France 24

25. Institute for Regenerative Medicine and Biotherapy, Université Montpellier, INSERM, CNRS, Montpellier, France 25

26. Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR 1163, Imagine Institute, Paris, France 26

27. Department of Neonatology, Centre Hospitalier de Polynésie Française, Papeete, French Polynesia 27

28. Precision Cancer Medicine Team, Institut Gustave Roussy, Villejuif, France 28

29. Pharmacology - Pharmacogenetic Department, Hopital Saint-Louis, Assistance Publique – Hôpitaux de Paris, Paris, France 29

30. Department of Environmental and Public Health Sciences, College of Medicine, University of Cincinnati, Cincinnati, OH 30

31. Tupua Tamasese Meaole Hospital, Apia, Samoa 31

32. School of Medicine, National University of Samoa, Apia, Samoa 32

33. Lutia i Puava ae Mapu i Fagalele, Apia, Samoa 33

34. Ministry of Health, Apia, Samoa 34

35. Queensland Children’s Hospital and University of Queensland, Brisbane, Queensland, Australia 35

36. Tumbatin Developmental Services, Sydney Children’s Hospital, Randwick, New South Wales, Australia 36

37. School of Women’s and Children’s Health, University of New South Wales, Sydney, New South Wales, Australia 37

38. Department of Forensic Pathology, Auckland City Hospital, Auckland, New Zealand 38

39. Clinical Geneticist, South Island Hub, Genetic Health Service, Christchurch, New Zealand 39

40. Department of Virology and Immunology, LabPLUS, Auckland City Hospital, Auckland, New Zealand 40

41. Department of Molecular Medicine and Pathology, Faculty of Medical and Health Science, University of Auckland, Auckland, New Zealand 41

42. Molecular Pathology, Canterbury Health Laboratories, Christchurch, New Zealand 42

43. The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK 43

44. Chemical Pathology and Genetics, Canterbury Health Laboratories, Christchurch, New Zealand 44

45. Department of Clinical Immunology, Auckland City Hospital, Auckland, New Zealand 45

46. Laboratory of Research on Infectious Vector-borne Diseases, Institut Louis Malardé, Papeete, French Polynesia 46

47. Garvan Institute of Medical Research, Sydney, Australia 47

48. St Vincent’s Clinical School, Faculty of Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia 48

49. Department of Immunology and Infectious Diseases, Sydney Children’s Hospital, Randwick, New South Wales, Australia 49

50. Howard Hughes Medical Institute, New York, NY 50

Abstract

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.

Funder

MATAEA

Institut Pasteur

Collège de France

Centre national de la recherche scientifique

Fondation Allianz-Institut de France

French Government’s Investissement d’Avenir program

Milieu Intérieur

Fondation de France

Fondation pour la Recherche Médicale

Howard Hughes Medical Institute

Rockefeller University

St. Giles Foundation

National Institutes of Health

National Center for Advancing Translational Sciences

NIH Clinical and Translational Science Award

Emergent Ventures

Mercatus Center at George Mason University

Yale Center for Mendelian Genomics

National Human Genome Research Institute

Yale High-Performance Computing Center

Fisher Center for Alzheimer’s Research Foundation

Meyer Foundation

French National Research Agency

Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence

FRM and ANR GENCOVID project

ANRS-COV05

ANR GENVIR

ANR AABIFNCOV

European Union’s Horizon 2020 research and innovation program

Square Foundation

Grandir - Fonds de solidarité pour l’enfance

Fondation du Souffle

SCOR Corporate Foundation for Science

Institut National de la Santé et de la Recherche Médicale

French Ministry of Higher Education, Research, and Innovation

University of Paris

Imagine Institute

Fondation Bettencourt-Schueller

Consejo Nacional de Ciencia y Technologia

Medical Research Council

International Center for Genetic Engineering and Biotechnology

National Health and Medical Research Council of Australia

John Brown Cook Foundation

National Heart, Lung and Blood Institute

Northwest Genomics Center

New York Genome Center

TOPMed Informatics Research Center

TOPMed Data Coordinating Center

Jeffrey Modell Foundation

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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