Heterozygous BTNL8 variants in individuals with multisystem inflammatory syndrome in children (MIS-C).

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; Elorrieta, Leire Estramiana; D'Souza, Giselle; Wright, Victoria J; Estrada-Rivadeneyra, Diego; Tremoulet, Adriana H; Dummer, Kirsten B; Netea, Stejara A; Condino-Neto, Antonio; Lau, Yu Lung; Cuadros, Esmeralda Núñez; Toubiana, Julie; Pena, Marisol Holanda; Rieux-Laucat, Frédéric; Luyt, Charles-Edouard; Haerynck, Filomeen; Mège, Jean Louis; Chakravorty, Samya; Haddad, Elie; Morin, Marie-Paule; Akcan, Özge Metin; Keles, Sevgi; Emiroglu, Melike; Alkan, Gulsum; Öz, Sadiye Kübra Tüter; Bozdemir, Sefika Elmas; 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; Aydin, Zeynep Gokce Gayretli; Bloomfield, Marketa; AlKhater, Suzan A; Cyrus, Cyril; Stepanovskiy, Yuriy; Bondarenko, Anastasiia; Öz, Fatma Nur; Polat, Meltem; Fremuth, Jiří; Lebl, Jan; Geraldo, Amyrath; Jouanguy, Emmanuelle; Effort, COVID-19 Human Genetic; DIAMONDS,; EUCLIDS,; Carter, Michael J; Wellman, Paul; Peters, Mark; de Diego, Rebeca Pérez; 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

doi:10.25418/crick.27908334.v1

Heterozygous BTNL8 variants in individuals with multisystem inflammatory syndrome in children (MIS-C).

journal contribution

posted on 2024-11-26, 10:42 authored by 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, COVID-19 Human Genetic Effort, DIAMONDS, EUCLIDS, 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

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.