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

7 Citations (Scopus)

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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
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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