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Heterozygous <i>BTNL8</i> variants in individuals with multisystem inflammatory syndrome in children (MIS-C)
Evangelos Bellos, David Santillo, Pierre Vantourout, Heather Jackson, Amédine Duret, Henry J. Hearn, Yoann Seeleuthner, Estelle Talouarn, Stephanie Hodeib, Harsita Patel, Oliver Powell, Sophya Yeoh, Dominic Habgood-Coote, Samuel J. Nichols, Leire Estramiana Elorrieta, Giselle D’Souza, Victoria Wright, Diego Estrada‐Rivadeneyra, Adriana H. Tremoulet, Kirsten Dummer, Stejara A. Netea, Antônio Condino‐Neto, YL Lau, Esmeralda Núñez Cuadros, Julie Toubiana, M.S. 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Borghesi, Amed Aziz Bousfiha, Daniel Blázquez‐Gamero, Petter Brodin, Giorgio Casari, Jacques Fellay, Carlos Flores, Guy Gorochov, Emine Hafize Erdeniz, Lennart Hammarström, Y. García, Adem Karbuz, Adam Klocperk, Paloma Lapuente-Suanzes, Davood Mansouri, Trine H. Mogensen, Lisa F. P. Ng, Antonio Novelli, Giuseppe Novelli, Keisuke Okamoto, Satoshi Okada, Qiang Pan‐Hammarström, Graziano Pesole, Laurent Rénia, Carlos Rodríguez‐Gallego, Anna Šedivá, Mohammad Shahrooei, Pere Soler‐Palacín, András N. Spaan, Gönül Tanır, Ahmad Abou Tayoun, Şehime Gülsün Temel, Donald C. Vinh, Aubrey J. 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Pollard, Mark Anthony, Sarah Hopton, Danielle Miller, Zoe Oliver, Sally Beer, Bryony Ward, Meeru Gurung, Puja Amatya, Bhishma Pokhrel, Sanjeev Man Bijukchhe, Madhav Chandra Gautam, Sarah Kelly, Peter O’Reilly, Sonu Shrestha, Federico Martinón‐Torres, Antonio Salas, Fernando Álvez González, Sonia Ares Gómez, Xabier Bello, Mirian Ben García, Fernando Caamaño Viña, Sandra Carnota, María José Currás-Tuala, Ana Dacosta Urbieta, Carlos Durán Suárez, Isabel Ferreirós-Vidal, Luisa García Vicente, Alberto Gómez‐Carballa, José Gómez Rial, Pilar Leboráns Iglesias, Narmeen Mallah, José María Martinón, Belén Mosquera Pérez Sánchez, Sara Pischedda, Sara Rey Vázquez, Irene Rivero‐Calle, Carmen Rodrı́guez-Tenreiro, Lorenzo Redondo-Collazo, Sonia Serén Fernández, Marisol Vilas Iglesias, Enitan D. Carrol, Elizabeth Cocklin, Rebecca Beckley, Abbey Bracken, Ceri Evans, Aakash Khanijau, Rebecca Lenihan, Nadia Lewis-Burke, Karen Newall, Sam Romaine, Jennifer Whitbread, Μαρία Τσολιά, Irini Eleftheriou, Νikos Spyridis, Maria Tambouratzi, Despoina Maritsi, Antonios Marmarinos, Marietta Xagorari, Lourida Panagiota, Pefanis Aggelos, Akinosoglou Karoli, Gogos Charalambos, Maragos Markos, Voulgarelis Michalis, S Ioan, Marieke Emonts, Emma Lim, John T. Isaacs, Kathryn Bell, Stephen Crulley, Daniel Fabián, Evelyn Thomson, Diane Wallia, Caroline Miller, Ashley Bell, Fabian van der Velden, Geoff Shenton, David Price, Owen Treloar, Daisy Thomas, Pablo Rojo, Cristina Epalza, Serena Villaverde, Sonia Márquez, Manuel Gijón, Fátima Machín, Laura Cabello, Irene Hernández, Lourdes Gutiérrez, Ángela Manzanares, Martijn van de Kuip, A. Marceline van Furth, J. Merlijn van den Berg, Giske Biesbroek, Floris Verkuil, Carlijn van der Zee, Dasja Pajkrt, Michaël Boele van Hensbroek, D. Schonenberg, Mariken Gruppen, Sietse Q. Nagelkerke, Machiel H. Jansen, Ines Goetschalckx, Lorenza Romani, Maia De Luca, Sara Chiurchiù, Costanza Tripiciano, Stefania Mercadante, Clementien L. Vermont, Henriëtte A. Moll, Dorine Borensztajn, Nienke N. Hagedoorn, Chantal Tan, Joany M. Zachariasse, W. Dik, Ching‐Fen Shen, Dace Zavadska, Sniedze Laivacuma, Aleksandra Rudzate, Diana Stoldere, Arta Barzdi, Elza Barzdi, Monta Madelāne, Dagne Grãvele, Dace Svilz, Romain Basmaci, Noémie Lachaume, Pauline Bories, RajaBen Tkhayat, Laura Chériaux, Juraté Davoust, Kim-Thanh Ong, Marie Cotillon, Thibault de Groc, Sébastien Lê, Nathalie Vergnault, Hélène See, Laure Cohen, Alice de Tugny, Névéna Danékova, Marine Mommert-Tripon, Karen Brengel‐Pesce, Marko Pokorn, Mojca Kolnik, Tadej Avčin, Tanja Avramoska, Natalija Bahovec, Petra Bogovič, Lidija Kitanovski, Mirijam Nahtigal, Lea Papst, Tina Plankar Srovin, Franc Strle, Katarina Vincek, Wim J. E. Tissing, Roelie M. Wösten‐van Asperen, Sebastiaan J. Vastert, Daniel C. Vijlbrief, Louis Bont, Coco R. Beudeker, Luregn J. Schlapbach, Christoph Aebi, Mariama Usman, Stefanie Schlüchter, Verena Wyss, Nina Schöbi, Elisa Zimmermann, Marion Meier, Kathrin Weber, Colin G. Fink, Marie Voice, Leo Calvo‐Bado, Michael Steele, Jennifer Holden, Andrew Taylor, Ronan Calvez, Catherine Davies, B. J. K. Evans, Jake Stevens, Peter Matthews, Kyle Billing, Alexander Binder, Daniela S. Kohlfürst, Nina A. Schweintzger, Christoph Zurl, Susanne Hösele, Manuel Leitner, Lena Pölz, Alexandra Rusu, Glorija Rajic, Bianca Stoiser, Martina Strempfl, Manfred G. Sagmeister, Sebastian Bauchinger, Martin Benesch, Astrid Ceolotto, Ernst Eber, Siegfried Gallistl, Harald Haidl, Almuthe Hauer, Christa Hude, Andreas Kapper, Markus Keldorfer, Sabine Löffler, Tobias Niedrist, Heidemarie Pilch, Andreas Pfleger, Klaus Pfurtscheller, Siegfried Rödl, Andrea Skrabl‐Baumgartner, Volker Strenger, Elmar Wallner, Maike K. Tauchert, Shunmay Yeung, Manuel Dewez, David Bath, Elizabeth Fitchett, Fiona V Cresswell, Effua Usuf, Kalifa Bojang, Anna Roca, Isatou Sarr, Momodou Saidykhan, Ebrahim Ndure, Ulrich von Both, Laura Kolberg, Patricia Schmied, Ioanna Mavridi, Irene Alba‐Alejandre, Nikolaus A. Haas, Esther M. Maier, Sabrina Juranek, Tobias Feuchtinger, Katharina Danhauser, Matthias Griese, Matthias Kappler, Eberhard Lurz, Sebastian Schroepf, Florian Hoffmann, Karl Reiter, Carola Schoen, Éric Giannoni, Martin Stocker, Klara M. Posfay‐Barbe, Ulrich Heininger, Anita Niederer-Loher, Christian R. Kahlert, Giancarlo Talucci, Christoph Berger, Thomas Riedel, Pedro Madrigal, Silvie Fexová, Michael Levin, Lachlan Coin, Bernardo Hourmat, Clive Hoggart, Amina Abdulla, Paul‐Michael Agapow, Maeve Bartlett, Hariklia Eleftherohorinou, David Inwald, Meg Mashbat, Simon Nadel, Rahmeen Rahman, Hannah Shailes, Clare Thakker, S Bokhandi, Sue Power, Heather Barham, Jenna Ridout, Sarah Thurston, Sanjay Patel, Jenni McCorkell, Patrick Davies, Lindsey Crate, Helen Navarra, Stephanie Carter, Raghu Ramaiah, Rekha Patel, Catherine Tuffrey, Andrew Gribbin, Sharon McCready, Katie Hardy, Fran Standing, Lauren O’Neill, Eugenia Abelake, Eniola Nsirim, Andrew J. Pollard, Louise Willis, Zoë Young, C. Royad, Sonia White, Peter‐Marc Fortune, Phil Hudnott, Ruth Barral‐Arca, Miriam Cebey‐López, Natalia García, Andrea Grela Beiroa, Antonio Justicia Grande, Alba‐Elena Martinez‐Santos, José María Martinón Sánchez, Beatriz Morillo-Gutiérrez, Belén Mosquera Pérez, Pablo Obando Pacheco, María del Sol Porto Silva, Ana Vega, Lucía Vilanova‐Trillo, Susana Beatriz Reyes, María Cruz León León, Álvaro Navarro Mingorance, Xavier Gabaldó Barrios, Eider Oñate Vergara, Ana Vivanco, Reyes Fernández, F. Giménez Sánchez, Miguel Forte, Jesús Ruíz-Contreras, Alba Palacios, Elisa Fernández-Cooke, Marisa Navarro, Cristina Álvarez Álvarez, María José Lozano, Eduardo Carreras, Sònia Brió Sanagustín, Olaf Neth, Maria del Carmen Martínez Padilla, Sara Guillén, Laura Fernández Silveira, David Moreno, Ronald de Groot, Navin P. Boeddha, Gertjan J. Driessen, Jan A. Hazelzet, Taco W. Kuijpers, Elisabeth A. M. Sanders, Diederik van de Beek, Arie van der Ende, Ria H.L.A. Philipsen, A. O. A. Adeel, Mijke A. Breukels, D. M. C. Brinkman, C. C. M. M. de Korte, Esther de Vries, Wouter J. de Waal, R. Dekkers, A. Dings-Lammertink, Rienus A. Doedens, Albertine E. Donker, M. Dousma, Tina E. Faber, G. P. J. M. Gerrits, J.A.M. Gerver, Jojanneke Heidema, J. Homan-van der Veen, Monique Jacobs, Nicolaas J. G. Jansen, P. Kawczynski, K. Klucovska, Martin C. J. Kneyber, Y. Koopman-Keemink, V. J. Langenhorst, J. Leusink, Bettina Loza, I. T. Merth, C.J. Miedema, C. Neeleman, Jeroen G. Noordzij, Charles C. Obihara, Ann Gils, G. H. Poortman, Stephanus T. Potgieter, J. Potjewijd, Tom Sprong, G. W. ten Tussher, Boony Thio, Gerdien A. Tramper‐Stranders, Marcel van Deuren, H. van der Meer, A. J. M. van Kuppevelt, Anne‐Marie van Wermeskerken, W. A. Verwijs, Tom F.W. Wolfs, Paul Hasters, Walter S. Baer, Hannah Frederick, Rebecca B. Jennings, Joanne Johnston, Rhian Kenwright, Elli Pinnock, Rachel Agbeko, Suzanne T. Anderson, Fatou Secka, Ngange Kebbeh, Gibbi Sey, Fatoumata Cole, Gilleh Thomas, Martín Antonio, Hinrich Baumgart, Markus R. Baumgartner, Uta Behrends, Ariane Biebl, Robert Birnbacher, Jan-Gerd Blanke, Carsten Boelke, Kai Breuling, Jürgen Brunner, Maria Buller, Peter Dahlem, Beate Dietrich, Johannes Elias, Josef Emhofer, Rosa Etschmaier, Sebastian Farr, Ylenia Girtler, Irina Grigorow, Konrad Heimann, Ulrike Ihm, Zdenek Jaros, Hermann Kalhoff, W Kaulfersch, Christoph Kemen, Nina Klocker, Bernhard Köster, Eleni Komini, Lydia Kramer, Antje Neubert, Daniel Ortner, Lydia Pescollderungg, Goran Ristić, Andrea Sellner, Astrid Sonnleitner, Matthias Sperl, Wolfgang Stelzl, Holger Till, Andreas Trobisch, Anne Vierzig, Ulrich Vogel, Christina Weingarten, Stefanie Welke, Andreas Wimmer, Uwe Wintergerst, Daniel Wüller, Andrew Zaunschirm, Ieva Ziuraite, Veslava Žukovskaja, Martin L. Hibberd, Sonia Dávila, Isabel Delany, Rebeca Pérez de Diego, Lindsey Edwards, Christopher Chiu, Mahdad Noursadeghi, Alexandre Bolze, Chisato Shimizu, Myrsini Kaforou, Melissa Shea Hamilton, Erica G. Schmitt, Agustí Rodríguez‐Palmero, Aurora Pujol, Jihoon Kim, Aurélie Cobat, Laurent Abel, Shen‐Ying Zhang, Jean‐Laurent Casanova, Jane C. Burns, Adrian Hayday
Bibliographic record
VenueThe Journal of Experimental Medicine · 2024
Typearticle
Languageen
FieldMedicine
TopicKawasaki Disease and Coronary Complications
Canadian institutionsUniversité de MontréalSickKids FoundationCentre Hospitalier Universitaire Sainte-JustineInstitute of Infection and ImmunityHospital for Sick Children
FundersEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNIHR Imperial Biomedical Research CentreEconomic and Social Research CouncilNational Center for Advancing Translational SciencesMedical Research CouncilHorizon 2020 Framework ProgrammeFondation pour la Recherche MédicaleNational Institutes of HealthRosetrees TrustEuropean CommissionAgència de Gestió d'Ajuts Universitaris i de RecercaSCOR Corporate Foundation for ScienceUniversity College LondonWellcome TrustCancer Research UKInstitut des maladies génétiques ImagineFrancis Crick InstituteCentres de Recerca de CatalunyaInstitut National de la Santé et de la Recherche MédicaleFondation du SouffleMeyer FoundationUK Research and InnovationRockefeller UniversitySt. Giles FoundationNational Institute of Allergy and Infectious DiseasesFisher Center for Alzheimer's Research FoundationAgence Nationale de la RechercheMinistère de l'Enseignement supérieur, de la Recherche et de l'InnovationImperial College LondonFundació la Marató de TV3Generalitat de CatalunyaNational Institute for Health and Care ResearchHoward Hughes Medical Institute
KeywordsEnteropathyBiologyIntestinal permeabilityHomeostasisInflammatory bowel diseaseImmunologyGeneInflammationDiseaseRegulatorGeneticsMedicineInternal medicineEndocrinology
Abstract
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.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
metaresearch head score (Codex)0.000
metaresearch head score (Gemma)0.001
Version: metacan-v3-hybrid-931329e0061cValidation status: machine_predicted_unvalidated
Candidate categoriesnone
Consensus categoriesnone
DomainCandidate signal: none · Consensus signal: none
Study designCandidate signal: Observational · Consensus signal: Observational
GenreCandidate signal: Empirical · Consensus signal: Empirical
Teacher disagreement score0.003
Threshold uncertainty score0.007
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
Opus teacher head0.012
GPT teacher head0.281
Teacher spread0.270 · how far apart the two teachers sit on this one work
Validation status
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
The models applied no category: nothing in the taxonomy fit this work.
Study designObservational
Domainnot available
GenreEmpirical
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".
Quick stats
Citations9
Published2024
Admission routes1
Has abstractyes