Heterozygous BTNL8 variants in individuals with multisystem inflammatory syndrome in children (MIS-C)
Authors: Bellos Evangelos , Santillo Dilys , Vantourout Pierre , Jackson Heather R. , Duret Amedine , Hearn Henry , Seeleuthner Yoann , Talouarn Estelle , Hodeib Stephanie , Patel Harsita , Powell Oliver , Yeoh Sophya , Mustafa Sobia , Habgood-Coote Dominic , Nichols Samuel , Estramiana Elorrieta Leire , D’Souza Giselle , Wright Victoria J. , Estrada-Rivadeneyra Diego , Tremoulet Adriana H. , Dummer Kirsten B. , Netea Stejara A. , Condino-Neto Antonio , Lau Yu Lung , Núñez Cuadros Esmeralda , Toubiana Julie , Holanda Pena Marisol , Rieux-Laucat Frédéric , Luyt Charles-Edouard , Haerynck Filomeen , Mège Jean Louis , Chakravorty Samya , Haddad Elie , Morin Marie-Paule , Metin Akcan Özge , Keles Sevgi , Emiroglu Melike , Alkan Gulsum , Tüter Öz Sadiye Kübra , Elmas Bozdemir Sefika , Morelle Guillaume , Volokha Alla , Kendir-Demirkol Yasemin , Sözeri Betul , Coskuner Taner , Yahsi Aysun , Gulhan Belgin , Kanik-Yuksek Saliha , Bayhan Gulsum Iclal , Ozkaya-Parlakay Aslinur , Yesilbas Osman , Hatipoglu Nevin , Ozcelik Tayfun , Belot Alexandre , Chopin Emilie , Barlogis Vincent , Sevketoglu Esra , Menentoglu Emin , Gayretli Aydin Zeynep Gokce , Bloomfield Marketa , AlKhater Suzan A. , Cyrus Cyril , Stepanovskiy Yuriy , Bondarenko Anastasiia , Öz Fatma Nur , Polat Meltem , Fremuth Jiří , Lebl Jan , Geraldo Amyrath , Jouanguy Emmanuelle ,   COVID-19 Human Genetic Effort, Aiuti Alessandro , Alsina Laia , Andreakos Evangelos , de Andrés Martín Ana , Biggs Catherine M. , Borghesi Alessandro , Bousfiha Amed Aziz , Blazquez-Gamero Daniel , Brodin Petter , Casari Giorgio , Condino-Neto Antonio , Fellay Jacques , Flores Carlos , Gorochov Guy , Erdeniz Emine Hafize , Hammarström Lennart , Garcia Yolanda Jordan , Karbuz Adem , Klocperk Adam , Lapuente-Suanzes Paloma , Lau Yu-Lung , Leung Cheng , Mansouri Davood , Mogensen Trine H. , Ng Lisa F.P. , Novelli Antonio , Novelli Giuseppe , Okamoto Keisuke , Okada Satoshi , Pan-Hammarström Qiang , Pesole Graziano , Renia Laurent , Rodriguez-Gallego Carlos , Sediva Anna , Shahrooei Mohammad , Soler-Palacin Pere , Spaan András N. , Tanir Gonul , Tayoun Ahmad Abou , Temel Şehime G. , Vinh Donald C. ,   DIAMONDS, Cunnington Aubrey , Herberg Jethro , Kaforou Myrsini , Wright Victoria J. , Bellos Evangelos , Broderick Claire , Channon-Wells Samuel , Cooray Samantha , De Tisham , D'Souza Giselle , Elorrieta Leire Estramia , Estrada-Rivadeneyra Diego , Galassini Rachel , Habgood-Coote Dominic , Hamilton Shea , Jackson Heather , Kavangh James , Keren Ila , Marjaneh Mahdi Moradi , Menikou Stephanie , Nichols Samuel , Nijman Ruud , Pennisi Ivana , Powell Oliver , Reid Ruth , Shah Priyen , Vito Ortensia , Whittaker Elizabeth , Wilson Clare , Womersley Rebecca , Abdulla Ami , Darnell Sarah , Mustafa Sobia , Georgiou Pantelis , Manzano Jesus-Rodriguez , Moser Nicolas , Carter Michael , Tibby Shane , Cohen Jonathan , Davis Francesca , Kenny Julia , Wellman Paul , White Marie , Fish Matthew , Jennings Aislinn , Shankar-Hari Manu , Fidler Katy , Agranoff Dan , Richmond Vivien , Seal Mathhew , Faust Saul , Owen Dan , Ensom Ruth , McKay Sarah , Shaji Mariya , Schranz Rachel , Rughni Prita , Anpanthar Amutha , Liebeschuetz Susan , Riddell Anna , Divakaran Divya , Han Louise , Khalid Nosheen , Malcolm Ivone Lancoma , Schofield Jessica , Simagan Teresa , Peters Mark , Bamford Alasdair , O'Neill Lauran , Pathan Nazima , Daubney Esther , White Deborah , Heightman Melissa , Eisen Sarah , Segal Terry , Wellings Lucy , Drysdale Simon B. , Branch Nicole , Hamzah Lisa , Jarman Heather , Nyirenda Maggie , Capozzi Lisa , Gardiner Emma , Moots Robert , Nasher Magda , Hanson Anita , Linforth Michelle , O'Riordan Sean , Ellis Don , Deep Akash , Caro Ivan , Shackley Fiona , Bellini Arianna , Gormley Stuart , Neshat Samira , Scholefield Barnaby , Robbins Ceri , Winmill Helen , Paulus Stéphane C. , Pollard Andrew J. , Anthony Mark , Hopton Sarah , Miller Danielle , Oliver Zoe , Beer Sally , Ward Bryony , Shrestha Shrija , Gurung Meeru , Amatya Puja , Pokhrel Bhishma , Bijukchhe Sanjeev Man , Gautam Madhav Chandra , Kelly Sarah , O'Reilly Peter , Shrestha Sonu , Martinón-Torres Federico , Salas Antonio , Álvez González Fernando , Gómez Sonia Ares , Bello Xabier , García Mirian Ben , Caamaño Viña Fernando , Carnota Sandra , Curras-Tuala María José , Dacosta Urbieta Ana , Suárez Carlos Durán , Vidal Isabel Ferreiros , Vicente Luisa García , Gómez-Carballa Alberto , Rial Jose Gómez , Iglesias Pilar Leboráns , Mallah Narmeen , Martinón-Torres Nazareth , Martinón José María , Mosquera Pérez Sánchez Belén , Pardo-Seco Jacobo , Pischedda Sara , Vázquez Sara Rey , Calle Irene Rivero , Rodríguez-Tenreiro Carmen , Redondo-Collazo Lorenzo , Fernández Sonia Serén , Iglesias Marisol Vilas , Carrol Enitan D. , Cocklin Elizabeth , Beckley Rebecca , Bracken Abbey , Evans Ceri , Khanijau Aakash , Lenihan Rebecca , Lewis-Burke Nadia , Newall Karen , Romaine Sam , Whitbread Jennifer , Tsolia Maria , Eleftheriou Irini , Spyridis Nikos , Tambouratzi Maria , Maritsi Despoina , Marmarinos Antonios , Xagorari Marietta , Panagiota Lourida , Aggelos Pefanis , Karoli Akinosoglou , Charalambos Gogos , Markos Maragos , Michalis Voulgarelis , Ioan Stergiou , Emonts Marieke , Lim Emma , Isaacs John , Bell Kathryn , Crulley Stephen , Fabian Daniel , Thomson Evelyn , Wallia Diane , Miller Caroline , Bell Ashley , van der Velden Fabian J.S. , Shenton Geoff , Price Ashley , Treloar Owen , Thomas Daisy , Rojo Pablo , Epalza Cristina , Villaverde Serena , Márquez Sonia , Gijón Manuel , Machín Fátima , Cabello Laura , Hernández Irene , Gutiérrez Lourdes , Manzanares Ángela , Kuijpers Taco W. , van de Kuip Martijn , van Furth Marceline , van den Berg Merlijn , Biesbroek Giske , Verkuil Floris , van der Zee Carlijn , Pajkrt Dasja , van Hensbroek Michael Boele , Schonenberg Dieneke , Gruppen Mariken , Nagelkerke Sietse , Jansen Machiel H. , Goetschalckx Ines , Romani Lorenza , De Luca Maia , Chiurchiù Sara , Tripiciano Costanza , Mercadante Stefania , Vermont Clementien L. , Moll Henriëtte A. , Borensztajn Dorine M. , Hagedoorn Nienke N. , Tan Chantal , Zachariasse Joany , Dik W. , Shen Ching-Fen , Zavadska Dace , Laivacuma Sniedze , Rudzate Aleksandra , Stoldere Diana , Barzdi Arta , Barzdi Elza , Madelane Monta , Gravele Dagne , Svilz Dace , Basmaci Romain , Lachaume Noémie , Bories Pauline , Tkhayat RajaBen , Chériaux Laura , Davoust Juraté , Ong Kim-Thanh , Cotillon Marie , de Groc Thibault , Le Sébastien , Vergnault Nathalie , Sée Hélène , Cohen Laure , de Tugny Alice , Danekova Nevena , Mommert-Tripon Marine , Brengel-Pesce Karen , Pokorn Marko , Kolnik Mojca , Avčin Tadej , Avramoska Tanja , Bahovec Natalija , Bogovič Petra , Kitanovski Lidija , Nahtigal Mirijam , Papst Lea , Plankar Srovin Tina , Strle Franc , Vincek Katarina , van der Flier Michiel , Tissing Wim J.E. , Wösten-van Asperen Roelie M. , Vastert Sebastiaan J. , Vijlbrief Daniel C. , Bont Louis J. , Beudeker Coco R. , Agyeman Philipp , Schlapbach Luregn , Aebi Christoph , Usman Mariama , Schlüchter Stefanie , Wyss Verena , Schöbi Nina , Zimmermann Elisa , Meier Marion , Weber Kathrin , Fink Colin , Voice Marie , Calvo-Bado Leo , Steele Michael , Holden Jennifer , Taylor Andrew , Calvez Ronan , Davies Catherine , Evans Benjamin , Stevens Jake , Matthews Peter , Billing Kyle , Zenz Werner , Binder Alexander , Kohlmaier Benno , Kohlfürst Daniela S. , Schweintzger Nina A. , Zurl Christoph , Hösele Susanne , Leitner Manuel , Pölz Lena , Rusu Alexandra , Rajic Glorija , Stoiser Bianca , Strempfl Martina , Sagmeister Manfred G. , Bauchinger Sebastian , Benesch Martin , Ceolotto Astrid , Eber Ernst , Gallistl Siegfried , Haidl Harald , Hauer Almuthe , Hude Christa , Kapper Andreas , Keldorfer Markus , Löffler Sabine , Niedrist Tobias , Pilch Heidemarie , Pfleger Andreas , Pfurtscheller Klaus , Rödl Siegfried , Skrabl-Baumgartner Andrea , Strenger Volker , Wallner Elmar , Tauchert Maike K. , Yeung Shunmay , Dewez Manuel , Bath David , Fitchett Elizabeth , Cresswell Fiona , Usuf Effua , Bojang Kalifa , Roca Anna , Sarr Isatou , Saidykhan Momodou , Ndure Ebrahim , von Both Ulrich , Kolberg Laura , Schmied Patricia , Mavridi Ioanna , Alba-Alejandre Irene , Haas Nikolaus , Maier Esther , Juranek Sabrina , Feuchtinger Tobias , Danhauser Katharina , Griese Matthias , Kappler Matthias , Lurz Eberhard , Schroepf Sebastian , Hoffmann Florian , Reiter Karl , Schoen Carola , Schlapbach Luregn J. , Giannoni Eric , Stocker Martin , Posfay-Barbe Klara M. , Heininger Ulrich , Bernhard-Stirnemann Sara , Niederer-Loher Anita , Kahlert Christian , Talucci Giancarlo , Relly Christa , Berger Christoph , Riedel Thomas , Madrigal Pedro , Fexova Silvie ,   EUCLIDS, Levin Michael , Coin Lachlan , Gormley Stuart , Hamilton Shea , Herberg Jethro , Hourmat Bernardo , Hoggart Clive , Kaforou Myrsini , Sancho-Shimizu Vanessa , Wright Victoria , Abdulla Amina , Agapow Paul , Bartlett Maeve , Bellos Evangelos , Eleftherohorinou Hariklia , Galassini Rachel , Inwald David , Mashbat Meg , Menikou Stephanie , Mustafa Sobia , Nadel Simon , Rahman Rahmeen , Shailes Hannah , Thakker Clare , Bokhandi Sumit , Power Sue , Barham Heather , Pathan Nazima , Ridout Jenna , White Deborah , Thurston Sarah , Faust Saul , Patel Sanjay , McCorkell Jenni , Davies Patrick , Crate Lindsey , Navarra Helen , Carter Stephanie , Ramaiah Raghu , Patel Rekha , Tuffrey Catherine , Gribbin Andrew , McCready Sharon , Peters Mark , Hardy Katie , Standing Fran , O'Neill Lauren , Abelake Eugenia , Deep Akash , Nsirim Eniola , Pollard Andrew , Willis Louise , Young Zoe , Royad Collin , White Sonia , Fortune Peter-Marc , Hudnott Phil , Martinón-Torres Federico , Salas Antonio , González Fernando Álvez , Barral-Arca Ruth , Cebey-López Miriam , Curras-Tuala María José , García Natalia , Vicente Luisa García , Gómez-Carballa Alberto , Rial Jose Gómez , Beiroa Andrea Grela , Grande Antonio Justicia , Leboráns Iglesias Pilar , Martínez Santos Alba Elena , Martinón-Torres Federico , Martinón-Torres Nazareth , Martinón Sánchez José María , Morillo Gutiérrez Beatriz , Mosquera Pérez Belén , Obando Pacheco Pablo , Pardo-Seco Jacobo , Pischedda Sara , Rivero-Calle Irene , Rodríguez-Tenreiro Carmen , Redondo-Collazo Lorenzo , Fernández Sonia Serén , del Sol Porto Silva María , Vega Ana , Trillo Lucía Vilanova , Reyes Susana Beatriz , León María Cruz León , Mingorance Álvaro Navarro , Barrios Xavier Gabaldó , Vergara Eider Oñate , Torre Andrés Concha , Vivanco Ana , Fernández Reyes , Sánchez Francisco Giménez , Forte Miguel Sánchez , Rojo Pablo , Contreras Jesus Ruiz , Palacios Alba , Ibarrondo Cristina Epalza , Cooke Elizabeth Fernández , Navarro Marisa , Álvarez Cristina Álvarez , Lozano María José , Carreras Eduardo , Sanagustín Sonia Brió , Neth Olaf , del Carmen Martínez Padilla Maria , Tato Luis Manuel Prieto , Guillén Sara , Silveira Laura Fernández , Moreno David , de Groot Ronald , van Furth A. Marceline Tutu , van der Flier Michiel , Boeddha Navin P. , Driessen Gertjan J.A. , Hazelzet Jan , Kuijpers Taco W. , Pajkrt Dasja , Sanders Elisabeth A.M. , van de Beek Diederik , van der Ende Arie , Philipsen Ria H.L.A. , Adeel Abdul O.A. , Breukels Mijke A. , Brinkman Danielle M.C. , de Korte Carla C.M.M. , de Vries Esther , de Waal Wouter J. , Dekkers Roel , Dings-Lammertink Anouk , Doedens Rienus A. , Donker Albertine E. , Dousma Mieke , Faber Tina E. , Gerrits Gerardus P.J.M. , Gerver Jan A.M. , Heidema Jojanneke , Homan-van der Veen Jenneke , Jacobs Monique A.M. , Jansen Nicolaas J.G. , Kawczynski Pawel , Klucovska Kristine , Kneyber Martin C.J. , Koopman-Keemink Yvonne , Langenhorst Veerle J. , Leusink José , Loza Bettina F. , Merth Istvan T. , Miedema Carien J. , Neeleman Chris , Noordzij Jeroen G. , Obihara Charles C. , van Overbeek - van Gils A. Lindy T. , Poortman Geriska H. , Potgieter Stephanus T. , Potjewijd Joke , Rosias Phillippe P.R. , Sprong Tom , ten Tussher Gavin W. , Thio Boony J. , Tramper-Stranders Gerdien A. , van Deuren Marcel , van der Meer Henny , van Kuppevelt Andre J.M. , van Wermeskerken Anne-Marie , Verwijs Wim A. , Wolfs Tom F.W. , Schlapbach Luregn J. , Agyeman Philipp , Aebi Christoph , Berger Christoph , Giannoni Eric , Stocker Martin , Posfay-Barbe Klara M. , Heininger Ulrich , Bernhard-Stirnemann Sara , Niederer-Loher Anita , Kahlert Christian , Hasters Paul , Relly Christa , Baer Walter , Carrol Enitan D. , Paulus Stéphane , Frederick Hannah , Jennings Rebecca , Johnston Joanne , Kenwright Rhian , Fink Colin G. , Pinnock Elli , Emonts Marieke , Agbeko Rachel , Anderson Suzanne , Secka Fatou , Bojang Kalifa , Sarr Isatou , Kebbeh Ngange , Sey Gibbi , Saidykhan Momodou , Cole Fatoumata , Thomas Gilleh , Antonio Martin , Zenz Werner , Kohlfürst Daniela S. , Binder Alexander , Schweintzger Nina A. , Sagmeister Manfred , Baumgart Hinrich , Baumgartner Markus , Behrends Uta , Biebl Ariane , Birnbacher Robert , Blanke Jan-Gerd , Boelke Carsten , Breuling Kai , Brunner Jürgen , Buller Maria , Dahlem Peter , Dietrich Beate , Eber Ernst , Elias Johannes , Emhofer Josef , Etschmaier Rosa , Farr Sebastian , Girtler Ylenia , Grigorow Irina , Heimann Konrad , Ihm Ulrike , Jaros Zdenek , Kalhoff Hermann , Kaulfersch Wilhelm , Kemen Christoph , Klocker Nina , Köster Bernhard , Kohlmaier Benno , Komini Eleni , Kramer Lydia , Neubert Antje , Ortner Daniel , Pescollderungg Lydia , Pfurtscheller Klaus , Reiter Karl , Ristic Goran , Rödl Siegfried , Sellner Andrea , Sonnleitner Astrid , Sperl Matthias , Stelzl Wolfgang , Till Holger , Trobisch Andreas , Vierzig Anne , Vogel Ulrich , Weingarten Christina , Welke Stefanie , Wimmer Andreas , Wintergerst Uwe , Wüller Daniel , Zaunschirm Andrew , Ziuraite Ieva , Žukovskaja Veslava , Hibberd Martin L. , Davila Sonia , Delany Isabel , Carter Michael J. , Wellman Paul , Peters Mark , Pérez de Diego Rebeca , Edwards Lindsey Ann , Chiu Christopher , Noursadeghi Mahdad , Bolze Alexandre , Shimizu Chisato , Kaforou Myrsini , Hamilton Melissa Shea , Herberg Jethro A. , Schmitt Erica G. , Rodriguez-Palmero Agusti , Pujol Aurora , Kim Jihoon , Cobat Aurélie , Abel Laurent , Zhang Shen-Ying , Casanova Jean-Laurent , Kuijpers Taco W. , Burns Jane C. , Levin Michael , Hayday Adrian C. , Sancho-Shimizu Vanessa 
Published: November 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 &lt; 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.