Avaliação de genes auto inflamatórios em crianças com Síndrome Inflamatória Multissistêmica Pediátrica (SIM-P) associada à infecção pelo SARS-CoV-2

Abstract

Introduction: Multisystem Inflammatory Syndrome in Children (MIS-C) is an inflammatory condition associated with SARS-CoV-2 infection. It is characterized by fever, prominent gastrointestinal symptoms, mucocutaneous manifestations, respiratory symptoms, and shock. The occurrence of P-MIS may be linked to innate immunological errors that selectively affect the host's immune response against SARS-CoV-2. Ain: Identify variants in genes involved in primary auto inflammatory conditions that may be implicated in MIS-C. Methods: Cells and clinical/laboratory information were collected from 21 pediatric patients with MIS-C recruited from three public hospitals in the Northeast region of Brazil. The MIS-C cases were categorized as severe or moderate based on the need for Positive Pressure Ventilation (PPV) and/or vasopressor medication, respectively. Subsequently, whole exome sequencing (WES) was performed on the individuals, and a strategy for prioritizing Single Nucleotide Variants (SNVs) with potential deleterious effects was applied. The focus was on 56 genes previously implicated in auto inflammatory diseases (according to the International Union of Immunological Societies Immunodeficiency Committee, 2022). Results: Nine individuals presented with the moderate form of MIS-C, while the remaining 12 were included in the severe MIS-C group. In the variant prioritization approach, six Single Nucleotide Variants (SNVs) were identified in five different genes (ADAM17, CARD14, IKBKG, PSTPIP1, and SH3BP12). All these variants were found in children/adolescents with the severe form of MIS-C. Notably, two variants (rs1200631089 and rs144458353) in the ADAM17 gene were selected. This gene encodes a protease implicated in the processing of tumor necrosis factor-alpha (TNF-α) and plays a crucial role in SARS-CoV-2 infection by cleaving Angiotensin-Converting Enzyme 2 (ACE2), the primary human receptor for SARS-CoV-2. Conclusion: Our data suggest that rare deleterious variants in genes previously implicated in auto inflammatory conditions, including ADAM17, IKBKG, PSTPIP1, SH3BP2, and CARD14, may account for the occurrence of P-MIS in previously healthy Brazilian children and adolescents.