Heterozygous <i>BTNL8</i> variants in individuals with multisystem inflammatory syndrome in children (MIS-C)
Authors: Evangelos Bellos, Dilys Santillo, Pierre Vantourout, Heather R. Jackson, Amedine Duret, Henry Hearn, Yoann Seeleuthner, Estelle Talouarn, Stephanie Hodeib, Harsita Patel, Oliver Powell, Sophya Yeoh, Sobia Mustafa, Dominic Habgood-Coote, Samuel Nichols, Leire Estramiana Elorrieta, Giselle D’Souza, Victoria J. Wright, Diego Estrada-Rivadeneyra, Adriana H. Tremoulet, Kirsten B. Dummer, Stejara A. Netea, Antonio Condino-Neto, Yu Lung Lau, Esmeralda Núñez Cuadros, Julie Toubiana, Marisol Holanda Pena, Frédéric Rieux-Laucat, Charles-Edouard Luyt, Filomeen Haerynck, Jean Louis Mège, Samya Chakravorty, Elie Haddad, Marie-Paule Morin, Özge Metin Akcan, Sevgi Keles, Melike Emiroglu, Gulsum Alkan, Sadiye Kübra Tüter Öz, Sefika Elmas Bozdemir, Guillaume Morelle, Alla Volokha, Yasemin Kendir-Demirkol, Betul Sözeri, Taner Coskuner, Aysun Yahsi, Belgin Gulhan, Saliha Kanik-Yuksek, Gulsum Iclal Bayhan, Aslinur Ozkaya-Parlakay, Osman Yesilbas, Nevin Hatipoglu, Tayfun Ozcelik, Alexandre Belot, Emilie Chopin, Vincent Barlogis, Esra Sevketoglu, Emin Menentoglu, Zeynep Gokce Gayretli Aydin, Marketa Bloomfield, Suzan A. AlKhater, Cyril Cyrus, Yuriy Stepanovskiy, Anastasiia Bondarenko, Fatma Nur Öz, Meltem Polat, Jiří Fremuth, Jan Lebl, Amyrath Geraldo, Emmanuelle Jouanguy, Alessandro Aiuti, Laia Alsina, Evangelos Andreakos, Ana de Andrés Martín, Catherine M. Biggs, Alessandro Borghesi, Amed Aziz Bousfiha, Daniel Blazquez-Gamero, Petter Brodin, Giorgio Casari, Antonio Condino-Neto, Jacques Fellay, Carlos Flores, Guy Gorochov, Emine Hafize Erdeniz, Lennart Hammarström, Yolanda Jordan Garcia, Adem Karbuz, Adam Klocperk, Paloma Lapuente-Suanzes, Yu-Lung Lau, Cheng Leung, Davood Mansouri, Trine H. Mogensen, Lisa F.P. Ng, Antonio Novelli, Giuseppe Novelli, Keisuke Okamoto, Satoshi Okada, Qiang Pan-Hammarström, Graziano Pesole, Laurent Renia, Carlos Rodriguez-Gallego, Anna Sediva, Mohammad Shahrooei, Pere Soler-Palacin, András N. Spaan, Gonul Tanir, Ahmad Abou Tayoun, Şehime G. Temel, Donald C. Vinh, Aubrey Cunnington, Jethro Herberg, Myrsini Kaforou, Victoria J. Wright, Evangelos Bellos, Claire Broderick, Samuel Channon-Wells, Samantha Cooray, Tisham De, Giselle D'Souza, Leire Estramia Elorrieta, Diego Estrada-Rivadeneyra, Rachel Galassini, Dominic Habgood-Coote, Shea Hamilton, Heather Jackson, James Kavangh, Ila Keren, Mahdi Moradi Marjaneh, Stephanie Menikou, Samuel Nichols, Ruud Nijman, Ivana Pennisi, Oliver Powell, Ruth Reid, Priyen Shah, Ortensia Vito, Elizabeth Whittaker, Clare Wilson, Rebecca Womersley, Ami Abdulla, Sarah Darnell, Sobia Mustafa, Pantelis Georgiou, Jesus-Rodriguez Manzano, Nicolas Moser, Michael Carter, Shane Tibby, Jonathan Cohen, Francesca Davis, Julia Kenny, Paul Wellman, Marie White, Matthew Fish, Aislinn Jennings, Manu Shankar-Hari, Katy Fidler, Dan Agranoff, Vivien Richmond, Mathhew Seal, Saul Faust, Dan Owen, Ruth Ensom, Sarah McKay, Mariya Shaji, Rachel Schranz, Prita Rughni, Amutha Anpanthar, Susan Liebeschuetz, Anna Riddell, Divya Divakaran, Louise Han, Nosheen Khalid, Ivone Lancoma Malcolm, Jessica Schofield, Teresa Simagan, Mark Peters, Alasdair Bamford, Lauran O'Neill, Nazima Pathan, Esther Daubney, Deborah White, Melissa Heightman, Sarah Eisen, Terry Segal, Lucy Wellings, Simon B. Drysdale, Nicole Branch, Lisa Hamzah, Heather Jarman, Maggie Nyirenda, Lisa Capozzi, Emma Gardiner, Robert Moots, Magda Nasher, Anita Hanson, Michelle Linforth, Sean O'Riordan, Don Ellis, Akash Deep, Ivan Caro, Fiona Shackley, Arianna Bellini, Stuart Gormley, Samira Neshat, Barnaby Scholefield, Ceri Robbins, Helen Winmill, Stéphane C. Paulus, Andrew J. Pollard, Mark Anthony, Sarah Hopton, Danielle Miller, Zoe Oliver, Sally Beer, Bryony Ward, Shrija Shrestha, 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 Curras-Tuala, Ana Dacosta Urbieta, Carlos Durán Suárez, Isabel Ferreiros Vidal, Luisa García Vicente, Alberto Gómez-Carballa, Jose Gómez Rial, Pilar Leboráns Iglesias, Narmeen Mallah, Nazareth Martinón-Torres, José María Martinón, Belén Mosquera Pérez Sánchez, Jacobo Pardo-Seco, Sara Pischedda, Sara Rey Vázquez, Irene Rivero Calle, Carmen Rodríguez-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, Maria Tsolia, Irini Eleftheriou, Nikos Spyridis, Maria Tambouratzi, Despoina Maritsi, Antonios Marmarinos, Marietta Xagorari, Lourida Panagiota, Pefanis Aggelos, Akinosoglou Karoli, Gogos Charalambos, Maragos Markos, Voulgarelis Michalis, Stergiou Ioan, Marieke Emonts, Emma Lim, John Isaacs, Kathryn Bell, Stephen Crulley, Daniel Fabian, Evelyn Thomson, Diane Wallia, Caroline Miller, Ashley Bell, Fabian J.S. van der Velden, Geoff Shenton, Ashley 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, Taco W. Kuijpers, Martijn van de Kuip, Marceline van Furth, Merlijn van den Berg, Giske Biesbroek, Floris Verkuil, Carlijn van der Zee, Dasja Pajkrt, Michael Boele van Hensbroek, Dieneke Schonenberg, Mariken Gruppen, Sietse Nagelkerke, Machiel H. Jansen, Ines Goetschalckx, Lorenza Romani, Maia De Luca, Sara Chiurchiù, Costanza Tripiciano, Stefania Mercadante, Clementien L. Vermont, Henriëtte A. Moll, Dorine M. Borensztajn, Nienke N. Hagedoorn, Chantal Tan, Joany Zachariasse, W. Dik, Ching-Fen Shen, Dace Zavadska, Sniedze Laivacuma, Aleksandra Rudzate, Diana Stoldere, Arta Barzdi, Elza Barzdi, Monta Madelane, Dagne Gravele, Dace Svilz, Romain Basmaci, Noémie Lachaume, Pauline Bories, RajaBen Tkhayat, Laura Chériaux, Juraté Davoust, Kim-Thanh Ong, Marie Cotillon, Thibault de Groc, Sébastien Le, Nathalie Vergnault, Hélène Sée, Laure Cohen, Alice de Tugny, Nevena Danekova, 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, Michiel van der Flier, Wim J.E. Tissing, Roelie M. Wösten-van Asperen, Sebastiaan J. Vastert, Daniel C. Vijlbrief, Louis J. Bont, Coco R. Beudeker, Philipp Agyeman, Luregn Schlapbach, Christoph Aebi, Mariama Usman, Stefanie Schlüchter, Verena Wyss, Nina Schöbi, Elisa Zimmermann, Marion Meier, Kathrin Weber, Colin Fink, Marie Voice, Leo Calvo-Bado, Michael Steele, Jennifer Holden, Andrew Taylor, Ronan Calvez, Catherine Davies, Benjamin Evans, Jake Stevens, Peter Matthews, Kyle Billing, Werner Zenz, Alexander Binder, Benno Kohlmaier, 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 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 Haas, Esther Maier, Sabrina Juranek, Tobias Feuchtinger, Katharina Danhauser, Matthias Griese, Matthias Kappler, Eberhard Lurz, Sebastian Schroepf, Florian Hoffmann, Karl Reiter, Carola Schoen, Luregn J. Schlapbach, Eric Giannoni, Martin Stocker, Klara M. Posfay-Barbe, Ulrich Heininger, Sara Bernhard-Stirnemann, Anita Niederer-Loher, Christian Kahlert, Giancarlo Talucci, Christa Relly, Christoph Berger, Thomas Riedel, Pedro Madrigal, Silvie Fexova, Michael Levin, Lachlan Coin, Stuart Gormley, Shea Hamilton, Jethro Herberg, Bernardo Hourmat, Clive Hoggart, Myrsini Kaforou, Vanessa Sancho-Shimizu, Victoria Wright, Amina Abdulla, Paul Agapow, Maeve Bartlett, Evangelos Bellos, Hariklia Eleftherohorinou, Rachel Galassini, David Inwald, Meg Mashbat, Stephanie Menikou, Sobia Mustafa, Simon Nadel, Rahmeen Rahman, Hannah Shailes, Clare Thakker, Sumit Bokhandi, Sue Power, Heather Barham, Nazima Pathan, Jenna Ridout, Deborah White, Sarah Thurston, Saul Faust, Sanjay Patel, Jenni McCorkell, Patrick Davies, Lindsey Crate, Helen Navarra, Stephanie Carter, Raghu Ramaiah, Rekha Patel, Catherine Tuffrey, Andrew Gribbin, Sharon McCready, Mark Peters, Katie Hardy, Fran Standing, Lauren O'Neill, Eugenia Abelake, Akash Deep, Eniola Nsirim, Andrew Pollard, Louise Willis, Zoe Young, Collin Royad, Sonia White, Peter-Marc Fortune, Phil Hudnott, Federico Martinón-Torres, Antonio Salas, Fernando Álvez González, Ruth Barral-Arca, Miriam Cebey-López, María José Curras-Tuala, Natalia García, Luisa García Vicente, Alberto Gómez-Carballa, Jose Gómez Rial, Andrea Grela Beiroa, Antonio Justicia Grande, Pilar Leboráns Iglesias, Alba Elena Martínez Santos, Federico Martinón-Torres, Nazareth Martinón-Torres, José María Martinón Sánchez, Beatriz Morillo Gutiérrez, Belén Mosquera Pérez, Pablo Obando Pacheco, Jacobo Pardo-Seco, Sara Pischedda, Irene Rivero-Calle, Carmen Rodríguez-Tenreiro, Lorenzo Redondo-Collazo, Sonia Serén Fernández, 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, Andrés Concha Torre, Ana Vivanco, Reyes Fernández, Francisco Giménez Sánchez, Miguel Sánchez Forte, Pablo Rojo, Jesus Ruiz Contreras, Alba Palacios, Cristina Epalza Ibarrondo, Elizabeth Fernández Cooke, Marisa Navarro, Cristina Álvarez Álvarez, María José Lozano, Eduardo Carreras, Sonia Brió Sanagustín, Olaf Neth, Maria del Carmen Martínez Padilla, Luis Manuel Prieto Tato, Sara Guillén, Laura Fernández Silveira, David Moreno, Ronald de Groot, A. Marceline Tutu van Furth, Michiel van der Flier, Navin P. Boeddha, Gertjan J.A. Driessen, Jan Hazelzet, Taco W. Kuijpers, Dasja Pajkrt, Elisabeth A.M. Sanders, Diederik van de Beek, Arie van der Ende, Ria H.L.A. Philipsen, Abdul O.A. Adeel, Mijke A. Breukels, Danielle M.C. Brinkman, Carla C.M.M. de Korte, Esther de Vries, Wouter J. de Waal, Roel Dekkers, Anouk Dings-Lammertink, Rienus A. Doedens, Albertine E. Donker, Mieke Dousma, Tina E. Faber, Gerardus P.J.M. Gerrits, Jan A.M. Gerver, Jojanneke Heidema, Jenneke Homan-van der Veen, Monique A.M. Jacobs, Nicolaas J.G. Jansen, Pawel Kawczynski, Kristine Klucovska, Martin C.J. Kneyber, Yvonne Koopman-Keemink, Veerle J. Langenhorst, José Leusink, Bettina F. Loza, Istvan T. Merth, Carien J. Miedema, Chris Neeleman, Jeroen G. Noordzij, Charles C. Obihara, A. Lindy T. van Overbeek - van Gils, Geriska H. Poortman, Stephanus T. Potgieter, Joke Potjewijd, Phillippe P.R. Rosias, Tom Sprong, Gavin W. ten Tussher, Boony J. Thio, Gerdien A. Tramper-Stranders, Marcel van Deuren, Henny van der Meer, Andre J.M. van Kuppevelt, Anne-Marie van Wermeskerken, Wim A. Verwijs, Tom F.W. Wolfs, Luregn J. Schlapbach, Philipp Agyeman, Christoph Aebi, Christoph Berger, Eric Giannoni, Martin Stocker, Klara M. Posfay-Barbe, Ulrich Heininger, Sara Bernhard-Stirnemann, Anita Niederer-Loher, Christian Kahlert, Paul Hasters, Christa Relly, Walter Baer, Enitan D. Carrol, Stéphane Paulus, Hannah Frederick, Rebecca Jennings, Joanne Johnston, Rhian Kenwright, Colin G. Fink, Elli Pinnock, Marieke Emonts, Rachel Agbeko, Suzanne Anderson, Fatou Secka, Kalifa Bojang, Isatou Sarr, Ngange Kebbeh, Gibbi Sey, Momodou Saidykhan, Fatoumata Cole, Gilleh Thomas, Martin Antonio, Werner Zenz, Daniela S. Kohlfürst, Alexander Binder, Nina A. Schweintzger, Manfred Sagmeister, Hinrich Baumgart, Markus Baumgartner, Uta Behrends, Ariane Biebl, Robert Birnbacher, Jan-Gerd Blanke, Carsten Boelke, Kai Breuling, Jürgen Brunner, Maria Buller, Peter Dahlem, Beate Dietrich, Ernst Eber, Johannes Elias, Josef Emhofer, Rosa Etschmaier, Sebastian Farr, Ylenia Girtler, Irina Grigorow, Konrad Heimann, Ulrike Ihm, Zdenek Jaros, Hermann Kalhoff, Wilhelm Kaulfersch, Christoph Kemen, Nina Klocker, Bernhard Köster, Benno Kohlmaier, Eleni Komini, Lydia Kramer, Antje Neubert, Daniel Ortner, Lydia Pescollderungg, Klaus Pfurtscheller, Karl Reiter, Goran Ristic, Siegfried Rödl, 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 Davila, Isabel Delany, Michael J. Carter, Paul Wellman, Mark Peters, Rebeca Pérez de Diego, Lindsey Ann Edwards, Christopher Chiu, Mahdad Noursadeghi, Alexandre Bolze, Chisato Shimizu, Myrsini Kaforou, Melissa Shea Hamilton, Jethro A. Herberg, Erica G. Schmitt, Agusti Rodriguez-Palmero, Aurora Pujol, Jihoon Kim, Aurélie Cobat, Laurent Abel, Shen-Ying Zhang, Jean-Laurent Casanova, Taco W. Kuijpers, Jane C. Burns, Michael Levin, Adrian C. Hayday, Vanessa Sancho-Shimizu
Journal: The Journal of Experimental Medicine (2024)

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.