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Review
. 2021 Dec 1;33(6):549-555.
doi: 10.1097/MOP.0000000000001061.

Host genetics of pediatric SARS-CoV-2 COVID-19 and multisystem inflammatory syndrome in children

Grant S Schulert  1   2 , Sydney A Blum  1 , Randy Q Cron  3
Affiliations
Review

Host genetics of pediatric SARS-CoV-2 COVID-19 and multisystem inflammatory syndrome in children

Grant S Schulert et al. Curr Opin Pediatr. .

Abstract

Purpose of review: This review is meant to describe the genetic associations with pediatric severe COVID-19 pneumonia and the postinfectious complication of the multisystem inflammatory syndrome in children (MIS-C). Multiple genetic approaches have been carried out, primarily in adults with extrapolation to children, including genome-wide association studies (GWAS), whole exome and whole genome sequencing (WES/WGS), and target gene analyses.

Recent findings: Data from adults with severe COVID-19 have identified genomic regions (human leukocyte antigen locus and 3p21.31) as potential risk factors. Genes related to viral entry into cells (ABO blood group locus, ACE2, TMPRS22) have been linked to severe COVID-19 patients by GWAS and target gene approaches. Type I interferon (e.g. IFNAR2) and antiviral gene (e.g. TLR7) associations have been identified by several genetic approaches in severe COVID-19. WES has noted associations with several immune regulatory genes (e.g. SOCS1). Target gene approaches have identified mutations in perforin-mediated cytolytic pathway genes in children and adults with severe COVID-19 and children with MIS-C.

Summary: Several genetic associations have been identified in individuals with severe COVID-19 and MIS-C via various genetic approaches. Broadly speaking, COVID-19 genetic associations include genes involved with antiviral functions, viral cell entry, immune regulation, chemotaxis of white blood cells, and lymphocyte cytolytic function.

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Conflict of interest statement

R.Q.C. has served as a consultant to Sobi, Novartis, Pfizer, and Sironax. R.Q.C. has received grant support from Sobi for investigator-initiated clinical trials. G.S.S. has received consulting fees from Novartis and Sobi.

Figures

Box 1
Box 1
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FIGURE 1
FIGURE 1
Genes involved in the perforin-mediated cytolytic pathway of cytotoxic CD8 T lymphocytes and natural killer cells. Mutations in perforin or genes involved in delivering and releasing perforin containing cytotoxic granules to the immunologic synapse (e.g. STX11) may contribute to a CSS-like hyperinflammatory state in children with severe COVID-19 and MIS-C. CSS, cytokine storm syndrome; MIS-C, multisystem inflammatory syndrome in children.
See this image and copyright information in PMC

References

    1. Henderson LA, Canna SW, Schulert GS, et al. . On the alert for cytokine storm: immunopathology in COVID-19. Arthritis Rheumatol 2020; 72:1059–1063. - PMC - PubMed
    1. Group TWREAfC-TRW. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19 a meta-analysis. JAMA 2020; 324:1330–1341. - PMC - PubMed
    1. Feldstein LR, Tenforde MW, Friedman KG, et al. . Characteristics and outcomes of US children and adolescents with Multisystem Inflammatory Syndrome in Children (MIS-C) compared with severe acute COVID-19. JAMA 2021; 325:1074–1087. - PMC - PubMed
    1. Fajgenbaum DC, June CH. Cytokine Storm. N Engl J Med 2020; 383:2255–2273. - PMC - PubMed
    1. Diorio C, Henrickson SE, Vella LA, et al. . Multisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS-CoV-2. J Clin Investig 2020; 130:5967–5975. - PMC - PubMed

    2. These 3 papars are some of the first reports exploring the pathophysiology of the host immune responses to pediatric COVID-19 and MIS-C. Lymphopenia and hypercytokinemia are notable.

Publication types

Supplementary concepts