Biology 2022, 11, 417. https://doi.org/10.3390/biology11030417 www.mdpi.com/journal/biology Article Hemophagocytic Lymphohistiocytosis Gene Variants in Multisystem Inflammatory Syndrome in Children Anshul Vagrecha 1,2, *, Mingce Zhang 3 , Suchitra Acharya 1,2 , Shannon Lozinsky 1,2 , Aaron Singer 4 , Chana Levine 1 , Maha Al‐Ghafry 1,2 , Carolyn Fein Levy 1,2 and Randy Q. Cron 3 1 Department of Pediatrics, Division of Hematology/Oncology and Cellular Therapy, Cohen Children’s Medical Center, New Hyde Park, NY 11040, USA; sacharya@northwell.edu (S.A.); slozinsky@northwell.edu (S.L.); clevine6@northwell.edu (C.L.); malghafry@northwell.edu (M.A.‐G.); clevy4@northwell.edu (C.F.L.) 2 Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA 3 Division of Pediatric Rheumatology, Children’s of Alabama, University of Alabama at Birmingham, Birmingham, AL 35233, USA; mzhang@peds.uab.edu (M.Z.); randycron@uabmc.edu (R.Q.C.) 4 Yeshiva College, Yeshiva University, New York, NY 10033, USA; alsinger@mail.yu.edu * Correspondence: avagrecha@northwell.edu Tel.: +1‐718‐470‐3460 Simple Summary: Children with a COVID‐19 infection are at risk of developing a novel syndrome called multisystem inflammatory syndrome in children (MIS‐C). This disease state is characterized by a high level of inflammation. It is unclear why only some children infected with SARS‐CoV‐2 later develop MIS‐C. There may be genetic risk factors for MIS‐C development, but none have previously been reported. We report genetic findings in a group of children with MIS‐C. Abstract: Multisystem inflammatory syndrome in children (MIS‐C) affects few children previously infected with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). In 2020, 45 children admitted to our hospital for MIS‐C underwent genetic screening with a commercial 109‐immune‐ gene panel. Thirty‐nine children were diagnosed with MIS‐C, and 25.4% of the 39 MIS‐C patients harbored rare heterozygous missense mutations either in primary hemophagocytic lymphohistiocytosis (pHLH) genes (LYST, STXBP2, PRF1, UNC13D, AP3B1) or the HLH‐associated gene DOCK8 (four variants). We demonstrate that foamy virus introduction of cDNA for the four DOCK8 variants into human NK‐92 natural killer (NK) cells led to decreased CD107a expression (degranulation) and decreased NK cell lytic function in vitro for each variant. Heterozygous carriers of missense mutations in pHLH genes and DOCK8 may serve as risk factors for development of MIS‐C among children previously infected with SARS‐CoV‐2. Keywords: MIS‐C; HLH; VUS; DOCK8 1. Introduction Multisystem inflammatory syndrome in children (MIS‐C) is a rare, delayed (~3–8 weeks postinfection) complication of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection in children. According to the United States Centers for Disease Control and Prevention (CDC), it is diagnosed in individuals < 21 years presenting with fever, multiorgan dysfunction (>2 organ systems), marked elevation in inflammatory biomarkers, and current or recent evidence of SARS‐CoV‐2 infection without other known etiologies [1]. Children with MIS‐C share clinical features with other inflammatory syndromes, such as primary hemophagocytic lymphohistiocytosis (pHLH), cytokine storm syndrome (CSS), and sepsis [2–5]. While MIS‐C is distinct from these clinical entities, there could be some potential overlap between the underlying immunologic signature of MIS‐C and the other conditions on this spectrum of hyperinflammatory Citation: Vagrecha, A.; Zhang, M.; Acharya, S.; Lozinsky, S.; Singer, A.; Levine, C.; Al‐Ghafry, M.; Fein Levy, C.; Cron, R.Q. Hemophagocytic Lymphohistiocytosis Gene Variants in Multi‐System Inflammatory Syndrome in Children. Biology 2022, 11, 417. https://doi.org/10.3390/ biology11030417 Academic Editor: David R. Greaves Received: 31 January 2022 Accepted: 7 March 2022 Published: 9 March 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/license s/by/4.0/).