tetano
Editor, Senior Moderator
J Exp Med
. 2024 Dec 2;221(12):e920240699.
doi: 10.1084/jem.20240699. Epub 2024 Nov 22. Heterozygous BTNL8 variants in individuals with multisystem inflammatory syndrome in children (MIS-C)
Evangelos Bellos[SUP] #[/SUP][SUP] 1 2 [/SUP], Dilys Santillo[SUP] #[/SUP][SUP] 1 2 3 [/SUP], Pierre Vantourout[SUP] 4 5 [/SUP], Heather R Jackson[SUP] 1 [/SUP], Amedine Duret[SUP] 1 [/SUP], Henry Hearn[SUP] 1 2 [/SUP], Yoann Seeleuthner[SUP] 6 7 [/SUP], Estelle Talouarn[SUP] 6 7 [/SUP], Stephanie Hodeib[SUP] 1 2 3 [/SUP], Harsita Patel[SUP] 1 [/SUP], Oliver Powell[SUP] 1 [/SUP], Sophya Yeoh[SUP] 1 [/SUP], Sobia Mustafa[SUP] 1 [/SUP], Dominic Habgood-Coote[SUP] 1 [/SUP], Samuel Nichols[SUP] 1 [/SUP], Leire Estramiana Elorrieta[SUP] 1 [/SUP], Giselle D'Souza[SUP] 1 [/SUP], Victoria J Wright[SUP] 1 [/SUP], Diego Estrada-Rivadeneyra[SUP] 1 [/SUP], Adriana H Tremoulet[SUP] 8 9 [/SUP], Kirsten B Dummer[SUP] 8 9 [/SUP], Stejara A Netea[SUP] 10 [/SUP], Antonio Condino-Neto[SUP] 11 [/SUP], Yu Lung Lau[SUP] 12 [/SUP], Esmeralda Núñez Cuadros[SUP] 13 [/SUP], Julie Toubiana[SUP] 14 [/SUP], Marisol Holanda Pena[SUP] 15 [/SUP], Frédéric Rieux-Laucat[SUP] 16 17 [/SUP], Charles-Edouard Luyt[SUP] 18 [/SUP], Filomeen Haerynck[SUP] 19 [/SUP], Jean Louis Mège[SUP] 20 [/SUP], Samya Chakravorty[SUP] 21 22 23 [/SUP], Elie Haddad[SUP] 24 25 26 [/SUP], Marie-Paule Morin[SUP] 26 [/SUP], Özge Metin Akcan[SUP] 27 [/SUP], Sevgi Keles[SUP] 28 [/SUP], Melike Emiroglu[SUP] 29 [/SUP], Gulsum Alkan[SUP] 29 [/SUP], Sadiye Kübra Tüter Öz[SUP] 29 [/SUP], Sefika Elmas Bozdemir[SUP] 28 [/SUP], Guillaume Morelle[SUP] 30 [/SUP], Alla Volokha[SUP] 31 [/SUP], Yasemin Kendir-Demirkol[SUP] 32 [/SUP], Betul Sözeri[SUP] 33 [/SUP], Taner Coskuner[SUP] 33 [/SUP], Aysun Yahsi[SUP] 34 [/SUP], Belgin Gulhan[SUP] 34 [/SUP], Saliha Kanik-Yuksek[SUP] 34 [/SUP], Gulsum Iclal Bayhan[SUP] 35 [/SUP], Aslinur Ozkaya-Parlakay[SUP] 35 [/SUP], Osman Yesilbas[SUP] 36 [/SUP], Nevin Hatipoglu[SUP] 37 [/SUP], Tayfun Ozcelik[SUP] 38 [/SUP], Alexandre Belot[SUP] 39 [/SUP], Emilie Chopin[SUP] 40 [/SUP], Vincent Barlogis[SUP] 41 [/SUP], Esra Sevketoglu[SUP] 42 [/SUP], Emin Menentoglu[SUP] 42 [/SUP], Zeynep Gokce Gayretli Aydin[SUP] 43 [/SUP], Marketa Bloomfield[SUP] 44 45 [/SUP], Suzan A AlKhater[SUP] 46 47 [/SUP], Cyril Cyrus[SUP] 48 [/SUP], Yuriy Stepanovskiy[SUP] 49 [/SUP], Anastasiia Bondarenko[SUP] 49 [/SUP], Fatma Nur Öz[SUP] 50 [/SUP], Meltem Polat[SUP] 51 [/SUP], Jiří Fremuth[SUP] 52 [/SUP], Jan Lebl[SUP] 53 [/SUP], Amyrath Geraldo[SUP] 6 7 54 55 56 57 [/SUP], Emmanuelle Jouanguy[SUP] 6 7 54 55 56 57 [/SUP]; COVID-19 Human Genetic Effort; DIAMONDS; EUCLIDS; Michael J Carter[SUP] 58 59 [/SUP], Paul Wellman[SUP] 58 [/SUP], Mark Peters[SUP] 60 61 [/SUP], Rebeca Pérez de Diego[SUP] 62 [/SUP], Lindsey Ann Edwards[SUP] 63 [/SUP], Christopher Chiu[SUP] 64 [/SUP], Mahdad Noursadeghi[SUP] 65 [/SUP], Alexandre Bolze[SUP] 66 [/SUP], Chisato Shimizu[SUP] 8 9 [/SUP], Myrsini Kaforou[SUP] 1 [/SUP], Melissa Shea Hamilton[SUP] 1 2 [/SUP], Jethro A Herberg[SUP] 1 [/SUP], Erica G Schmitt[SUP] 67 [/SUP], Agusti Rodriguez-Palmero[SUP] 54 68 69 [/SUP], Aurora Pujol[SUP] 68 69 70 [/SUP], Jihoon Kim[SUP] 71 72 [/SUP], Aurélie Cobat[SUP] 6 7 55 [/SUP], Laurent Abel[SUP] 6 7 55 [/SUP], Shen-Ying Zhang[SUP] 6 7 55 [/SUP], Jean-Laurent Casanova[SUP] 6 7 55 56 57 [/SUP], Taco W Kuijpers[SUP] 10 73 [/SUP], Jane C Burns[SUP] 8 9 [/SUP], Michael Levin[SUP] 1 [/SUP], Adrian C Hayday[SUP] 4 5 [/SUP], Vanessa Sancho-Shimizu[SUP] 1 2 3 [/SUP]
Collaborators, Affiliations
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.
. 2024 Dec 2;221(12):e920240699.
doi: 10.1084/jem.20240699. Epub 2024 Nov 22. Heterozygous BTNL8 variants in individuals with multisystem inflammatory syndrome in children (MIS-C)
Evangelos Bellos[SUP] #[/SUP][SUP] 1 2 [/SUP], Dilys Santillo[SUP] #[/SUP][SUP] 1 2 3 [/SUP], Pierre Vantourout[SUP] 4 5 [/SUP], Heather R Jackson[SUP] 1 [/SUP], Amedine Duret[SUP] 1 [/SUP], Henry Hearn[SUP] 1 2 [/SUP], Yoann Seeleuthner[SUP] 6 7 [/SUP], Estelle Talouarn[SUP] 6 7 [/SUP], Stephanie Hodeib[SUP] 1 2 3 [/SUP], Harsita Patel[SUP] 1 [/SUP], Oliver Powell[SUP] 1 [/SUP], Sophya Yeoh[SUP] 1 [/SUP], Sobia Mustafa[SUP] 1 [/SUP], Dominic Habgood-Coote[SUP] 1 [/SUP], Samuel Nichols[SUP] 1 [/SUP], Leire Estramiana Elorrieta[SUP] 1 [/SUP], Giselle D'Souza[SUP] 1 [/SUP], Victoria J Wright[SUP] 1 [/SUP], Diego Estrada-Rivadeneyra[SUP] 1 [/SUP], Adriana H Tremoulet[SUP] 8 9 [/SUP], Kirsten B Dummer[SUP] 8 9 [/SUP], Stejara A Netea[SUP] 10 [/SUP], Antonio Condino-Neto[SUP] 11 [/SUP], Yu Lung Lau[SUP] 12 [/SUP], Esmeralda Núñez Cuadros[SUP] 13 [/SUP], Julie Toubiana[SUP] 14 [/SUP], Marisol Holanda Pena[SUP] 15 [/SUP], Frédéric Rieux-Laucat[SUP] 16 17 [/SUP], Charles-Edouard Luyt[SUP] 18 [/SUP], Filomeen Haerynck[SUP] 19 [/SUP], Jean Louis Mège[SUP] 20 [/SUP], Samya Chakravorty[SUP] 21 22 23 [/SUP], Elie Haddad[SUP] 24 25 26 [/SUP], Marie-Paule Morin[SUP] 26 [/SUP], Özge Metin Akcan[SUP] 27 [/SUP], Sevgi Keles[SUP] 28 [/SUP], Melike Emiroglu[SUP] 29 [/SUP], Gulsum Alkan[SUP] 29 [/SUP], Sadiye Kübra Tüter Öz[SUP] 29 [/SUP], Sefika Elmas Bozdemir[SUP] 28 [/SUP], Guillaume Morelle[SUP] 30 [/SUP], Alla Volokha[SUP] 31 [/SUP], Yasemin Kendir-Demirkol[SUP] 32 [/SUP], Betul Sözeri[SUP] 33 [/SUP], Taner Coskuner[SUP] 33 [/SUP], Aysun Yahsi[SUP] 34 [/SUP], Belgin Gulhan[SUP] 34 [/SUP], Saliha Kanik-Yuksek[SUP] 34 [/SUP], Gulsum Iclal Bayhan[SUP] 35 [/SUP], Aslinur Ozkaya-Parlakay[SUP] 35 [/SUP], Osman Yesilbas[SUP] 36 [/SUP], Nevin Hatipoglu[SUP] 37 [/SUP], Tayfun Ozcelik[SUP] 38 [/SUP], Alexandre Belot[SUP] 39 [/SUP], Emilie Chopin[SUP] 40 [/SUP], Vincent Barlogis[SUP] 41 [/SUP], Esra Sevketoglu[SUP] 42 [/SUP], Emin Menentoglu[SUP] 42 [/SUP], Zeynep Gokce Gayretli Aydin[SUP] 43 [/SUP], Marketa Bloomfield[SUP] 44 45 [/SUP], Suzan A AlKhater[SUP] 46 47 [/SUP], Cyril Cyrus[SUP] 48 [/SUP], Yuriy Stepanovskiy[SUP] 49 [/SUP], Anastasiia Bondarenko[SUP] 49 [/SUP], Fatma Nur Öz[SUP] 50 [/SUP], Meltem Polat[SUP] 51 [/SUP], Jiří Fremuth[SUP] 52 [/SUP], Jan Lebl[SUP] 53 [/SUP], Amyrath Geraldo[SUP] 6 7 54 55 56 57 [/SUP], Emmanuelle Jouanguy[SUP] 6 7 54 55 56 57 [/SUP]; COVID-19 Human Genetic Effort; DIAMONDS; EUCLIDS; Michael J Carter[SUP] 58 59 [/SUP], Paul Wellman[SUP] 58 [/SUP], Mark Peters[SUP] 60 61 [/SUP], Rebeca Pérez de Diego[SUP] 62 [/SUP], Lindsey Ann Edwards[SUP] 63 [/SUP], Christopher Chiu[SUP] 64 [/SUP], Mahdad Noursadeghi[SUP] 65 [/SUP], Alexandre Bolze[SUP] 66 [/SUP], Chisato Shimizu[SUP] 8 9 [/SUP], Myrsini Kaforou[SUP] 1 [/SUP], Melissa Shea Hamilton[SUP] 1 2 [/SUP], Jethro A Herberg[SUP] 1 [/SUP], Erica G Schmitt[SUP] 67 [/SUP], Agusti Rodriguez-Palmero[SUP] 54 68 69 [/SUP], Aurora Pujol[SUP] 68 69 70 [/SUP], Jihoon Kim[SUP] 71 72 [/SUP], Aurélie Cobat[SUP] 6 7 55 [/SUP], Laurent Abel[SUP] 6 7 55 [/SUP], Shen-Ying Zhang[SUP] 6 7 55 [/SUP], Jean-Laurent Casanova[SUP] 6 7 55 56 57 [/SUP], Taco W Kuijpers[SUP] 10 73 [/SUP], Jane C Burns[SUP] 8 9 [/SUP], Michael Levin[SUP] 1 [/SUP], Adrian C Hayday[SUP] 4 5 [/SUP], Vanessa Sancho-Shimizu[SUP] 1 2 3 [/SUP]
Collaborators, Affiliations
- PMID: 39576310
- DOI: 10.1084/jem.20240699
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.