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We sequenced 154 MIS-C patients and utilized a novel statistical framework of gene burden analysis, \u201cburdenMC,\u201d which identified an enrichment for rare predicted-deleterious variants in BTNL8 (OR = 4.2, 95% CI: 3.5\u20135.3, P &amp;lt; 10\u22126). BTNL8 encodes an intestinal epithelial regulator of V\u03b34+\u03b3\u03b4 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 V\u03b34+\u03b3\u03b4 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.<\/jats:p>","DOI":"10.1084\/jem.20240699","type":"journal-article","created":{"date-parts":[[2024,9,28]],"date-time":"2024-09-28T02:20:49Z","timestamp":1727490049000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":14,"title":["Heterozygous\n                    <i>BTNL8<\/i>\n                    variants in individuals with multisystem inflammatory syndrome in children (MIS-C)"],"prefix":"10.1084","volume":"221","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3389-5715","authenticated-orcid":true,"given":"Evangelos","family":"Bellos","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/041kmwe10","id-type":"ROR","asserted-by":"publisher"}],"name":"Imperial College London 1 Section of Paediatric Infectious Disease, 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