Multisystem inflammatory syndrome in children (MIS-C) is a rare condition following SARS-CoV-2 infection associated with intestinal manifestations. Genetic predisposition, including inborn errors of the OAS-RNAseL pathway, has been reported. We sequenced 154 MIS-C patients and utilized a novel statistical framework of gene burden analysis, "burdenMC," which identified an enrichment for rare predicted-deleterious variants in BTNL8 (OR = 4.2, 95% CI: 3.5-5.3, P < 10-6). BTNL8 encodes an intestinal epithelial regulator of Vγ4+γδ T cells implicated in regulating gut homeostasis. Enrichment was exclusive to MIS-C, being absent in patients with COVID-19 or bacterial disease. Using an available functional test for BTNL8, rare variants from a larger cohort of MIS-C patients (n = 835) were tested which identified eight variants in 18 patients (2.2%) with impaired engagement of Vγ4+γδ T cells. Most of these variants were in the B30.2 domain of BTNL8 implicated in sensing epithelial cell status. These findings were associated with altered intestinal permeability, suggesting a possible link between disrupted gut homeostasis and MIS-C-associated enteropathy triggered by SARS-CoV-2.

Aix Marseille University APHM Marseille France

Biocon Bristol Myers Squibb Research and Development Center Syngene Intl Ltd Bengaluru India

Bristol Myers Squibb Lawrenceville NJ USA

Catalan Institution of Research and Advanced Studies Barcelona Spain

CBC BIOTEC Biobank GHE Hospices Civils de Lyon Lyon France

Centre for Biomedical Research on Rare Diseases Instituto de Salud Carlos 3 Madrid Spain

Centre for Paediatrics and Child Health Faculty of Medicine Imperial College London London UK

Centre Host Microbiome Interactions Faculty of Dentistry Oral and Craniofacial Sciences King's College London Guy's Tower Guy's Hospital London UK

CHU Sainte Justine Azrieli Research Center Montreal Canada

College of Medicine Imam Abdulrahman Bin Faisal University Dammam Saudi Arabia

Department of Biochemistry College of Medicine Imam Abdulrahman Bin Faisal University Dammam Saudi Arabia

Department of Biomedical Informatics University of California San Diego CA USA

Department of General Paediatrics Hôpital Bicêtre AP HP University of Paris Saclay Le Kremlin Bicêtre France

Department of General Pediatrics and Infectious Diseases Necker Enfants Malades University Hospital AP HP Université Paris Cité Paris France

Department of Immunology 2nd Faculty of Medicine Charles University Prague and Motol University Hospital Prague Czech Republic

Department of Immunology Institute of Biomedical Sciences University of Sao Paulo Sao Paulo Brazil

Department of Infectious Disease Imperial College London London UK

Department of Microbiology Infectious Diseases and Immunology University of Montreal Montreal Canada

Department of Molecular Biology and Genetics Bilkent University Ankara Turkey

Department of Molecular Hematology Sanquin Research and Landsteiner Laboratory at the AmsterdamUMC Amsterdam Institute for Infection and Immunity AmsterdamUMC University of Amsterdam Amsterdam The Netherlands

Department of Paediatrics 1st Faculty of Medicine Charles University Prague and Thomayer University Hospital Prague Czech Republic

Department of Paediatrics and Adolescent Medicine LKS Faculty of Medicine The University of Hong Kong Pokfulam Hong Kong

Department of Pediatircs Germans Trias i Pujol Research Institute Universitat Autònoma de Barcelona Barcelona Spain

Department of Pediatric Genetics Umraniye Education and Research Hospital Health Sciences University İstanbul Turkey

Department of Pediatric Immunology Rheumatology and Infectious Disease Emma Children's Hospital Amsterdam University Medical Center University of Amsterdam Amsterdam The Netherlands

Department of Pediatric Infectious Disease SBU Ankara Dr Sami Ulus Maternity Child Health and Diseases Training and Research Hospital Ankara Turkey

Department of Pediatric Infectious Diseases Ankara City Hospital Ankara Turkey

Department of Pediatric Infectious Diseases Gazi University School of Medicine Ankara Turkey

Department of Pediatrics 2nd Faculty of Medicine Charles University Prague and Motol University Hospital Prague Czech Republic

Department of Pediatrics Immunology Infectious and Rare Diseases at the International European University Kyiv Ukraine

Department of Pediatrics Kawasaki Disease Research Center University of California San Diego La Jolla CA USA

Department of Pediatrics King Fahad Hospital of the University Al Khobar Saudi Arabia

Department of Pediatrics Necker Hospital for Sick Children Paris France

Department of Pediatrics PICU Faculty of Medicine in Pilsen Charles University Prague Prague Czech Republic

Department of Pediatrics Regional University Hospital of Málaga IBIMA Research Institute Málaga Spain

Department of Pediatrics University of Montreal Montreal Canada

Department of Women and Children's Health School of Life Course Sciences King's College London St Thomas' Hospital London UK

Division of Infection and Immunity University College London London UK

Division of Pediatric Allergy and Immunology Meram Medical Faculty Necmettin Erbakan University Konya Turkey

Division of Pediatric Critical Care Medicine Department of Pediatrics Faculty of Medicine Karadeniz Technical University Trabzon Turkey

Division of Pediatric Infectious Disease Department of Pediatrics Faculty of Medicine Karadeniz Technical University Trabzon Turkey

Division of Pediatric Infectious Diseases Department of Pediatrics Selcuk University Faculty of Medicine Konya Turkey

Division of Pediatric Infectious Diseases Medical Faculty Necmettin Erbakan University Konya Turkey

Division of Pediatric Rheumatology Umraniye Training and Research Hospital University of Health Sciences Istanbul Turkey

Division of Rheumatology and Immunology Department of Pediatrics Washington University in St Louis St Louis MO USA

Emory University Department of Pediatrics and Human Genetics Atlanta GA USA

Ghent Univer sity Hospital Ghent Belgium

Helix San Mateo CA USA

Hospital Universitario Marqués de Valdecilla Santander Spain

Howard Hughes Medical Institute Rockefeller University New York NY USA

Imagine Institute Paris Descartes Sorbonne Université Paris Cité Paris France

Imagine Institute Université Paris Cité Paris France

Immunosurveillance Laboratory The Francis Crick Institute London UK

Intensive Care Unit AP HP Pitié Salpêtrière Hospital Paris University Paris France

La Timone Children Hospital Aix Marseille University APHM Marseille France

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

Laboratory of Immunogenetics of Human Diseases IdiPAZ Institute for Health Research University Hospital La Paz Madrid Spain

Laboratory of Immunogenetics of Pediatric Autoimmune Diseases INSERM UMR 1163 Institut Imagine Paris France

Neurometabolic Diseases Laboratory Bellvitge Biomedical Research Institute Barcelona Spain

Paediatric Intensive Care Evelina London Children's Hospital Guy's and St Thomas' NHS Foundation Trust London UK

Paediatric Intensive Care Unit Great Ormond Street Hospital for Children NHS Foundation Trust and NIHR Biomedical Research Centre London UK

Pediatric Infectious Disease and Pediatric Immunology Department Shupyk National Healthcare University Kyiv Ukraine

Pediatric Infectious Diseases Unit Bakirkoy Dr Sadi Konuk Training and Research Hospital University of Health Sciences Istanbul Turkey

Peter Gorer Department of Immunobiology School of Immunology and Microbial Sciences King's College London London UK

Rady Children's Hospital San Diego San Diego CA USA

Section of Biomedical Informatics and Data Science Yale School of Medicine New Haven CT USA

Section of Paediatric Infectious Disease Department of Infectious Disease Faculty of Medicine Imperial College London London UK

Section of Virology Department of Infectious Disease Faculty of Medicine Imperial College London London UK

Service de Rhumatologie Pédiatrique Hôpital Femme Mère Enfant Groupement Hospitalier Est Bâtiment Pinel Bron France

St Giles Laboratory of Human Genetics of Infectious Diseases Rockefeller Branch The Rockefeller University New York NY USA

Univeristy of Health Sciences Turkiye Bakirkoy Dr Sadi Konuk Research and Training Hospital Pediatirc Intensive Care Department Istanbul Türkiye

University College London Great Ormond St Institute of Child Health London UK

Yildirim Beyazit University Ankara City Hospital Ankara Turkey

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