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Lookup NU author(s): Professor Marieke Emonts-le ClercqORCiD
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© 2024 Bellos et al.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.
Author(s): Bellos E, Santillo D, Vantourout P, Jackson HR, Duret A, Hearn H, Seeleuthner Y, Talouarn E, Hodeib S, Patel H, Powell O, Yeoh S, Mustafa S, Habgood-Coote D, Nichols S, Elorrieta LE, D'Souza G, Wright VJ, Estrada-Rivadeneyra D, Tremoulet AH, Dummer KB, Netea SA, Condino-Neto A, Lau YL, Cuadros EN, Toubiana J, Pena MH, Rieux-Laucat F, Luyt C-E, Haerynck F, Mege JL, Chakravorty S, Haddad E, Morin M-P, Akcan OM, Keles S, Emiroglu M, Alkan G, Oz SKT, Bozdemir SE, Morelle G, Volokha A, Kendir-Demirkol Y, Sozeri B, Coskuner T, Yahsi A, Gulhan B, Kanik-Yuksek S, Bayhan GI, Ozkaya-Parlakay A, Yesilbas O, Hatipoglu N, Ozcelik T, Belot A, Chopin E, Barlogis V, Sevketoglu E, Menentoglu E, Aydin ZGG, Bloomfield M, AlKhater SA, Cyrus C, Stepanovskiy Y, Bondarenko A, Oz FN, Polat M, Fremuth J, Lebl J, Geraldo A, Jouanguy E, Carter MJ, Wellman P, Peters M, de Diego RP, Edwards LA, Chiu C, Noursadeghi M, Bolze A, Shimizu C, Kaforou M, Hamilton MS, Herberg JA, Schmitt EG, Rodriguez-Palmero A, Pujol A, Kim J, Cobat A, Abel L, Zhang S-Y, Casanova J-L, Kuijpers TW, Burns JC, Levin M, Hayday AC, Sancho-Shimizu V, COVID-19 Human Genetic Effort, DIAMONDS Consortium, EUCLIDS Consortium, Emonts M
Publication type: Article
Publication status: Published
Journal: Journal of Experimental Medicine
Year: 2024
Volume: 221
Issue: 12
Print publication date: 01/12/2024
Online publication date: 22/11/2024
Acceptance date: 27/09/2024
Date deposited: 28/01/2025
ISSN (print): 0022-1007
ISSN (electronic): 1540-9538
Publisher: Rockefeller University Press
URL: https://doi.org/10.1084/jem.20240699
DOI: 10.1084/jem.20240699
PubMed id: 39576310
Notes: Professor Marieke Emonts is part of both EUCLIDS and DIAMONDS Consortia.
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