Heterozygous BTNL8 variants in individuals with multisystem inflammatory syndrome in children (MIS-C).
Creators: name: Bellos, Evangelos
name: Santillo, Dilys
name: Vantourout, Pierre
name: Jackson, Heather R
name: Duret, Amedine
name: Hearn, Henry
name: Seeleuthner, Yoann
name: Talouarn, Estelle
name: Hodeib, Stephanie
name: Patel, Harsita
name: Powell, Oliver
name: Yeoh, Sophya
name: Mustafa, Sobia
name: Habgood-Coote, Dominic
name: Nichols, Samuel
name: Elorrieta, Leire Estramiana
name: D'Souza, Giselle
name: Wright, Victoria J
name: Estrada-Rivadeneyra, Diego
name: Tremoulet, Adriana H
name: Dummer, Kirsten B
name: Netea, Stejara A
name: Condino-Neto, Antonio
name: Lau, Yu Lung
name: Cuadros, Esmeralda Núñez
name: Toubiana, Julie
name: Pena, Marisol Holanda
name: Rieux-Laucat, Frédéric
name: Luyt, Charles-Edouard
name: Haerynck, Filomeen
name: Mège, Jean Louis
name: Chakravorty, Samya
name: Haddad, Elie
name: Morin, Marie-Paule
name: Akcan, Özge Metin
name: Keles, Sevgi
name: Emiroglu, Melike
name: Alkan, Gulsum
name: Öz, Sadiye Kübra Tüter
name: Bozdemir, Sefika Elmas
name: Morelle, Guillaume
name: Volokha, Alla
name: Kendir-Demirkol, Yasemin
name: Sözeri, Betul
name: Coskuner, Taner
name: Yahsi, Aysun
name: Gulhan, Belgin
name: Kanik-Yuksek, Saliha
name: Bayhan, Gulsum Iclal
name: Ozkaya-Parlakay, Aslinur
name: Yesilbas, Osman
name: Hatipoglu, Nevin
name: Ozcelik, Tayfun
name: Belot, Alexandre
name: Chopin, Emilie
name: Barlogis, Vincent
name: Sevketoglu, Esra
name: Menentoglu, Emin
name: Aydin, Zeynep Gokce Gayretli
name: Bloomfield, Marketa
name: AlKhater, Suzan A
name: Cyrus, Cyril
name: Stepanovskiy, Yuriy
name: Bondarenko, Anastasiia
name: Öz, Fatma Nur
name: Polat, Meltem
name: Fremuth, Jiří
name: Lebl, Jan
name: Geraldo, Amyrath
name: Jouanguy, Emmanuelle
name: Effort, COVID-19 Human Genetic
name: DIAMONDS
name: EUCLIDS
name: Carter, Michael J
name: Wellman, Paul
name: Peters, Mark
name: de Diego, Rebeca Pérez
name: Edwards, Lindsey Ann
name: Chiu, Christopher
name: Noursadeghi, Mahdad
name: Bolze, Alexandre
name: Shimizu, Chisato
name: Kaforou, Myrsini
name: Hamilton, Melissa Shea
name: Herberg, Jethro A
name: Schmitt, Erica G
name: Rodriguez-Palmero, Agusti
name: Pujol, Aurora
name: Kim, Jihoon
name: Cobat, Aurélie
name: Abel, Laurent
name: Zhang, Shen-Ying
name: Casanova, Jean-Laurent
name: Kuijpers, Taco W
name: Burns, Jane C
name: Levin, Michael
name: Hayday, Adrian C
name: Sancho-Shimizu, Vanessa
Publisher: name: The Francis Crick Institute
Year: 2024
Subjects: classificationCode: Immunology
subject: Immunology
subject: FOS: Clinical medicine
classificationCode: Human Biology & Physiology
subject: Human Biology &amp; Physiology
classificationCode: Model organisms
subject: Model organisms

description: 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.