Heterozygous BTNL8 variants in individuals with multisystem inflammatory syndrome in children (MIS-C)Bellos, Evangelos (Avtor) Santillo, Dilys (Avtor) Vantourout, Pierre (Avtor) Jackson, Heather R. (Avtor) Duret, Amedine (Avtor) Hearn, Henry (Avtor) Seeleuthner, Yoann (Avtor) Talouarn, Estelle (Avtor) Hodeib, Stephanie (Avtor) Patel, Harsita (Avtor) Pokorn, Marko (Sodelavec pri raziskavi) Kolnik, Mojca (Sodelavec pri raziskavi) Avčin, Tadej (Avtor) Avramoska, Tanja (Sodelavec pri raziskavi) Bahovec, Natalija (Sodelavec pri raziskavi) Bogovič, Petra (Sodelavec pri raziskavi) Kitanovski, Lidija (Sodelavec pri raziskavi) Nahtigal Klevišar, Mirijam (Sodelavec pri raziskavi) Papst, Lea (Sodelavec pri raziskavi) Plankar Srovin, Tina (Sodelavec pri raziskavi) Strle, Franc (Sodelavec pri raziskavi) Vincek, Katarina (Avtor) human diseases geneticsInfectious diseases and host defenseinnate immunity and inflammationSARS-Cov-2Multisystem 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-2.20242025-12-02 13:35:54Neznano24493UDK: 616-097ISSN pri članku: 1540-9538DOI: 10.1084/jem.20240699COBISS_ID: 230729475sl