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

Evangelos Bellos; Dilys Santillo; Pierre Vantourout; DIAMONDS Consortium; Dace Zavadska; Sniedze Laivacuma; Aleksandra Rudzāte; Diāna Stoldere; Monta Madelāne; Dagne Grāvele; COVID-19 Human Genetic Effort; EUCLIDS Group

doi:10.1084/jem.20240699

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

Evangelos Bellos, Dilys Santillo, Pierre Vantourout, DIAMONDS Consortium, Dace Zavadska (Member of the Working Group), Sniedze Laivacuma (Member of the Working Group), Aleksandra Rudzāte (Member of the Working Group), Diāna Stoldere (Member of the Working Group), Monta Madelāne (Member of the Working Group), Dagne Grāvele (Member of the Working Group), COVID-19 Human Genetic Effort, EUCLIDS Group

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

1 Citation (Scopus)

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
Publication status	Published - Dec 2024
Externally published	Yes

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

Field of Science*

3.2 Clinical medicine

Publication Type*

1.1. Scientific article indexed in Web of Science and/or Scopus database

Access to Document

10.1084/jem.20240699Licence: CC BY

Heterozygous BTNL8 variants in individuals with multisystem inflammatory syndrome in childrenFinal published version, 6.23 MBLicence: CC BY

Cite this

Bellos, E., Santillo, D., Vantourout, P., DIAMONDS Consortium, Zavadska, D., Laivacuma, S., Rudzāte, A., Stoldere, D., Madelāne, M., Grāvele, D., COVID-19 Human Genetic Effort, & EUCLIDS Group (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{443c88320dec405fa64154726bcaa160,

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 = "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 = "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 Saliha Kanik-Yuksek and Bayhan, {Gulsum Iclal} and Aslinur Ozkaya-Parlakay and Vanessa Sancho-Shimizu and {DIAMONDS Consortium} and Dace Zavadska and Sniedze Laivacuma and Aleksandra Rudzāte and Diāna Stoldere and Monta Madelāne and Dagne Grāvele and {COVID-19 Human Genetic Effort} and {EUCLIDS Group}",

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

year = "2024",

month = dec,

doi = "10.1084/jem.20240699",

language = "English",

volume = "221",

journal = "Journal of Experimental Medicine",

issn = "0022-1007",

publisher = "Rockefeller University Press",

number = "12",

}

Bellos, E, Santillo, D, Vantourout, P, DIAMONDS Consortium, Zavadska, D , Laivacuma, S , Rudzāte, A , Stoldere, D , Madelāne, M, Grāvele, D, COVID-19 Human Genetic Effort & EUCLIDS Group 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 - 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 - Kanik-Yuksek, Saliha

AU - Bayhan, Gulsum Iclal

AU - Ozkaya-Parlakay, Aslinur

AU - Sancho-Shimizu, Vanessa

AU - DIAMONDS Consortium

AU - COVID-19 Human Genetic Effort

AU - EUCLIDS Group

A2 - Zavadska, Dace

A2 - Laivacuma, Sniedze

A2 - Rudzāte, Aleksandra

A2 - Stoldere, Diāna

A2 - Madelāne, Monta

A2 - Grāvele, Dagne

PY - 2024/12

Y1 - 2024/12

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 - https://www-webofscience-com.db.rsu.lv/wos/alldb/full-record/WOS:001394497700001

UR - https://pubmed.ncbi.nlm.nih.gov/39576310/

U2 - 10.1084/jem.20240699

DO - 10.1084/jem.20240699

M3 - Article

C2 - 39576310

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)

Abstract

Keywords*

Field of Science*

Publication Type*

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