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

COVID-19 Human Genetic Effort; 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; Michael J Carter; Lindsey Ann Edwards; Adrian C Hayday

doi:10.1084/jem.20240699

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

COVID-19 Human Genetic Effort, 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-RivadeneyraAdriana 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, Michael J Carter, Lindsey Ann Edwards, Adrian C Hayday

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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
Journal	The Journal of experimental medicine
Volume	221
Issue number	12
DOIs	https://doi.org/10.1084/jem.20240699
Publication status	Published - 2 Dec 2024

Keywords

Humans
COVID-19/genetics
Child
Systemic Inflammatory Response Syndrome/genetics
Male
Female
Butyrophilins/genetics
SARS-CoV-2
Child, Preschool
Heterozygote
Adolescent
Genetic Predisposition to Disease
Infant

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1084/jem.20240699Licence: CC BY

Heterozygous BTNL8 variant_BELLOS_Publishedonline2December2024_GOLD VoR (CC BY)Final published version, 6.23 MBLicence: CC BY

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COVID-19 Human Genetic Effort, 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., Estramiana Elorrieta, L., D'Souza, G., Wright, V. J., ... Hayday, A. C. (2024). Heterozygous BTNL8 variants in individuals with multisystem inflammatory syndrome in children (MIS-C). The Journal of experimental medicine, 221(12). https://doi.org/10.1084/jem.20240699

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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 = "Humans, COVID-19/genetics, Child, Systemic Inflammatory Response Syndrome/genetics, Male, Female, Butyrophilins/genetics, SARS-CoV-2, Child, Preschool, Heterozygote, Adolescent, Genetic Predisposition to Disease, Infant",

author = "{COVID-19 Human Genetic Effort} and 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 {Estramiana Elorrieta}, Leire and Giselle D'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 {N{\'u}{\~n}ez Cuadros}, Esmeralda and Julie Toubiana and {Holanda Pena}, Marisol and Fr{\'e}d{\'e}ric Rieux-Laucat and Charles-Edouard Luyt and Filomeen Haerynck and M{\`e}ge, {Jean Louis} and Samya Chakravorty and Elie Haddad and Marie-Paule Morin and {Metin Akcan}, {\"O}zge and Sevgi Keles and Melike Emiroglu and Gulsum Alkan and {T{\"u}ter {\"O}z}, {Sadiye K{\"u}bra} and {Elmas Bozdemir}, Sefika 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 Carter, {Michael J} and Edwards, {Lindsey Ann} and Hayday, {Adrian C}",

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doi = "10.1084/jem.20240699",

language = "English",

volume = "221",

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COVID-19 Human Genetic Effort, 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, Estramiana Elorrieta, L, D'Souza, G, Wright, VJ, Estrada-Rivadeneyra, D, Tremoulet, AH, Dummer, KB, Netea, SA, Condino-Neto, A, Lau, YL, Núñez Cuadros, E, Toubiana, J, Holanda Pena, M, Rieux-Laucat, F, Luyt, C-E, Haerynck, F, Mège, JL, Chakravorty, S, Haddad, E, Morin, M-P, Metin Akcan, Ö, Keles, S, Emiroglu, M, Alkan, G, Tüter Öz, SK, Elmas Bozdemir, S, Morelle, G, Volokha, A, Kendir-Demirkol, Y, Sözeri, B, Coskuner, T, Yahsi, A, Gulhan, B, Carter, MJ , Edwards, LA & Hayday, AC 2024, 'Heterozygous BTNL8 variants in individuals with multisystem inflammatory syndrome in children (MIS-C)', The Journal of experimental medicine, vol. 221, no. 12. https://doi.org/10.1084/jem.20240699

TY - JOUR

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

AU - COVID-19 Human Genetic Effort

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 - Estramiana Elorrieta, Leire

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 - Núñez Cuadros, Esmeralda

AU - Toubiana, Julie

AU - Holanda Pena, Marisol

AU - Rieux-Laucat, Frédéric

AU - Luyt, Charles-Edouard

AU - Haerynck, Filomeen

AU - Mège, Jean Louis

AU - Chakravorty, Samya

AU - Haddad, Elie

AU - Morin, Marie-Paule

AU - Metin Akcan, Özge

AU - Keles, Sevgi

AU - Emiroglu, Melike

AU - Alkan, Gulsum

AU - Tüter Öz, Sadiye Kübra

AU - Elmas Bozdemir, Sefika

AU - Morelle, Guillaume

AU - Volokha, Alla

AU - Kendir-Demirkol, Yasemin

AU - Sözeri, Betul

AU - Coskuner, Taner

AU - Yahsi, Aysun

AU - Gulhan, Belgin

AU - Carter, Michael J

AU - Edwards, Lindsey Ann

AU - Hayday, Adrian C

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 - Humans

KW - COVID-19/genetics

KW - Child

KW - Systemic Inflammatory Response Syndrome/genetics

KW - Male

KW - Female

KW - Butyrophilins/genetics

KW - SARS-CoV-2

KW - Child, Preschool

KW - Heterozygote

KW - Adolescent

KW - Genetic Predisposition to Disease

KW - Infant

UR - http://www.scopus.com/inward/record.url?scp=85210466949&partnerID=8YFLogxK

U2 - 10.1084/jem.20240699

DO - 10.1084/jem.20240699

M3 - Article

C2 - 39576310

SN - 0022-1007

VL - 221

JO - The Journal of experimental medicine

JF - The Journal of experimental medicine

IS - 12

ER -

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

Abstract

Keywords

UN SDGs

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