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

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 Mége; 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; 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

doi:10.1084/jem.20240699

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

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 Mége, 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, 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

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

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.

Original language	English
Article number	e920240699
Journal	Journal of Experimental Medicine
Volume	221
Issue number	12
DOIs	https://doi.org/10.1084/jem.20240699
State	Published - Dec 2 2024

Keywords

Human disease genetics
Infectious disease and host defense
Innate immunity and inflammation

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10.1084/jem.20240699

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Bellos, E., Santillo, D., Vantourout, P., Jackson, H. R., Duret, A., Hearn, H., Seeleuthner, Y., Talouarn, E., Hodeib, S., Patel, H., Powell, O., Yeoh, S., Mustafa, S., Habgood-Coote, D., Nichols, S., Elorrieta, L. E., D’Souza, G., Wright, V. J., Estrada-Rivadeneyra, D., ... Sancho-Shimizu, V. (2024). Heterozygous BTNL8 variants in individuals with multisystem inflammatory syndrome in children (MIS-C). Journal of Experimental Medicine, 221(12), Article e920240699. https://doi.org/10.1084/jem.20240699

@article{546eef881d794066ad9887e12315166e,

title = "Heterozygous BTNL8 variants in individuals with multisystem inflammatory syndrome in children (MIS-C)",

abstract = "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.",

keywords = "Human disease genetics, Infectious disease and host defense, Innate immunity and inflammation",

author = "Evangelos Bellos and Dilys Santillo and Pierre Vantourout and Jackson, \{Heather R.\} and Amedine Duret and Henry Hearn and Yoann Seeleuthner and Estelle Talouarn and Stephanie Hodeib and Harsita Patel and Oliver Powell and Sophya Yeoh and Sobia Mustafa and Dominic Habgood-Coote and Samuel Nichols and Elorrieta, \{Leire Estramiana\} and Giselle D{\textquoteright}Souza and Wright, \{Victoria J.\} and Diego Estrada-Rivadeneyra and Tremoulet, \{Adriana H.\} and Dummer, \{Kirsten B.\} and Netea, \{Stejara A.\} and Antonio Condino-Neto and Lau, \{Yu Lung\} and Cuadros, \{Esmeralda N{\'u}{\~n}ez\} and Julie Toubiana and Pena, \{Marisol Holanda\} and Fr{\'e}d{\'e}ric Rieux-Laucat and Luyt, \{Charles Edouard\} and Filomeen Haerynck and M{\'e}ge, \{Jean Louis\} and Samya Chakravorty and Elie Haddad and Morin, \{Marie Paule\} and Akcan, \{{\"O}zge Metin\} and Sevgi Keles and Melike Emiroglu and Gulsum Alkan and {\"O}z, \{Sadiye K{\"u}bra T{\"u}ter\} and Bozdemir, \{Sefika Elmas\} and Guillaume Morelle and Alla Volokha and Yasemin Kendir-Demirkol and Betul S{\"o}zeri and Taner Coskuner and Aysun Yahsi and Belgin Gulhan and Saliha Kanik-Yuksek and Bayhan, \{Gulsum Iclal\} and Aslinur Ozkaya-Parlakay and Osman Yesilbas and Nevin Hatipoglu and Tayfun Ozcelik and Alexandre Belot and Emilie Chopin and Vincent Barlogis and Esra Sevketoglu and Emin Menentoglu and Aydin, \{Zeynep Gokce Gayretli\} and Marketa Bloomfield and AlKhater, \{Suzan A.\} and Cyril Cyrus and Yuriy Stepanovskiy and Anastasiia Bondarenko and {\"O}z, \{Fatma Nur\} and Meltem Polat and Ji{\v r}{\'i} Fremuth and Jan Lebl and Amyrath Geraldo and Emmanuelle Jouanguy and Carter, \{Michael J.\} and Paul Wellman and Mark Peters and \{de Diego\}, \{Rebeca P{\'e}rez\} and Edwards, \{Lindsey Ann\} and Christopher Chiu and Mahdad Noursadeghi and Alexandre Bolze and Chisato Shimizu and Myrsini Kaforou and Hamilton, \{Melissa Shea\} and Herberg, \{Jethro A.\} and Schmitt, \{Erica G.\} and Agusti Rodriguez-Palmero and Aurora Pujol and Jihoon Kim and Aur{\'e}lie Cobat and Laurent Abel and Zhang, \{Shen Ying\} and Casanova, \{Jean Laurent\} and Kuijpers, \{Taco W.\} and Burns, \{Jane C.\} and Michael Levin and Hayday, \{Adrian C.\} and Vanessa Sancho-Shimizu",

note = "Publisher Copyright: {\textcopyright} 2024 Bellos et al.",

year = "2024",

month = dec,

day = "2",

doi = "10.1084/jem.20240699",

language = "English",

volume = "221",

journal = "Journal of Experimental Medicine",

issn = "0022-1007",

number = "12",

}

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, CE, Haerynck, F, Mége, JL, Chakravorty, S, Haddad, E, Morin, MP, Akcan, ÖM, Keles, S, Emiroglu, M, Alkan, G, Öz, SKT, Bozdemir, SE, Morelle, G, Volokha, A, Kendir-Demirkol, Y, Sözeri, 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, Öz, 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, SY, Casanova, JL, Kuijpers, TW, Burns, JC, Levin, M, Hayday, AC & Sancho-Shimizu, V 2024, 'Heterozygous BTNL8 variants in individuals with multisystem inflammatory syndrome in children (MIS-C)', Journal of Experimental Medicine, vol. 221, no. 12, e920240699. https://doi.org/10.1084/jem.20240699

TY - JOUR

T1 - Heterozygous BTNL8 variants in individuals with multisystem inflammatory syndrome in children (MIS-C)

AU - Bellos, Evangelos

AU - Santillo, Dilys

AU - Vantourout, Pierre

AU - Jackson, Heather R.

AU - Duret, Amedine

AU - Hearn, Henry

AU - Seeleuthner, Yoann

AU - Talouarn, Estelle

AU - Hodeib, Stephanie

AU - Patel, Harsita

AU - Powell, Oliver

AU - Yeoh, Sophya

AU - Mustafa, Sobia

AU - Habgood-Coote, Dominic

AU - Nichols, Samuel

AU - Elorrieta, Leire Estramiana

AU - D’Souza, Giselle

AU - Wright, Victoria J.

AU - Estrada-Rivadeneyra, Diego

AU - Tremoulet, Adriana H.

AU - Dummer, Kirsten B.

AU - Netea, Stejara A.

AU - Condino-Neto, Antonio

AU - Lau, Yu Lung

AU - Cuadros, Esmeralda Núñez

AU - Toubiana, Julie

AU - Pena, Marisol Holanda

AU - Rieux-Laucat, Frédéric

AU - Luyt, Charles Edouard

AU - Haerynck, Filomeen

AU - Mége, Jean Louis

AU - Chakravorty, Samya

AU - Haddad, Elie

AU - Morin, Marie Paule

AU - Akcan, Özge Metin

AU - Keles, Sevgi

AU - Emiroglu, Melike

AU - Alkan, Gulsum

AU - Öz, Sadiye Kübra Tüter

AU - Bozdemir, Sefika Elmas

AU - Morelle, Guillaume

AU - Volokha, Alla

AU - Kendir-Demirkol, Yasemin

AU - Sözeri, Betul

AU - Coskuner, Taner

AU - Yahsi, Aysun

AU - Gulhan, Belgin

AU - Kanik-Yuksek, Saliha

AU - Bayhan, Gulsum Iclal

AU - Ozkaya-Parlakay, Aslinur

AU - Yesilbas, Osman

AU - Hatipoglu, Nevin

AU - Ozcelik, Tayfun

AU - Belot, Alexandre

AU - Chopin, Emilie

AU - Barlogis, Vincent

AU - Sevketoglu, Esra

AU - Menentoglu, Emin

AU - Aydin, Zeynep Gokce Gayretli

AU - Bloomfield, Marketa

AU - AlKhater, Suzan A.

AU - Cyrus, Cyril

AU - Stepanovskiy, Yuriy

AU - Bondarenko, Anastasiia

AU - Öz, Fatma Nur

AU - Polat, Meltem

AU - Fremuth, Jiří

AU - Lebl, Jan

AU - Geraldo, Amyrath

AU - Jouanguy, Emmanuelle

AU - Carter, Michael J.

AU - Wellman, Paul

AU - Peters, Mark

AU - de Diego, Rebeca Pérez

AU - Edwards, Lindsey Ann

AU - Chiu, Christopher

AU - Noursadeghi, Mahdad

AU - Bolze, Alexandre

AU - Shimizu, Chisato

AU - Kaforou, Myrsini

AU - Hamilton, Melissa Shea

AU - Herberg, Jethro A.

AU - Schmitt, Erica G.

AU - Rodriguez-Palmero, Agusti

AU - Pujol, Aurora

AU - Kim, Jihoon

AU - Cobat, Aurélie

AU - Abel, Laurent

AU - Zhang, Shen Ying

AU - Casanova, Jean Laurent

AU - Kuijpers, Taco W.

AU - Burns, Jane C.

AU - Levin, Michael

AU - Hayday, Adrian C.

AU - Sancho-Shimizu, Vanessa

PY - 2024/12/2

Y1 - 2024/12/2

N2 - 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.

AB - 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.

KW - Human disease genetics

KW - Infectious disease and host defense

KW - Innate immunity and inflammation

UR - https://www.scopus.com/pages/publications/85210466949

U2 - 10.1084/jem.20240699

DO - 10.1084/jem.20240699

M3 - Article

C2 - 39576310

AN - SCOPUS:85210466949

SN - 0022-1007

VL - 221

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

IS - 12

M1 - e920240699

ER -

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

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