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

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.

Hemophagocytic Lymphohistiocytosis Gene Variants in Multisystem Inflammatory Syndrome in Children

“…Therefore, rare heterozygous missense variants in DOCK8 and pHLH genes (PRF1, UNC13D, STXBP2, AP3B1, and LYST) in our MIS-C cohort may have contributed to the CSS pathology of these patients in a threshold model of disease, where a combination of severe infection and a baseline genetic partial defect in perforin-mediated cytolysis result in excess proinflammatory cytokine production [28]. Heterozygous pathogenic missense mutations in pHLH or DOCK8 may thus contribute to MIS-C pathology via a partial dominant-negative fashion [37].…”

A Rare STXBP2 Mutation in Severe COVID-19 and Secondary Cytokine Storm Syndrome

“…Differences in haplotypes of killer-cell immune-globulin-like receptors (KIRs) has been shown to be informative of disease course, with the KIR2DS2/HLA C1 function unit protective against COVID-19 adverse outcomes [25]. Conversely, heterozygous mutations, largely missense, in pHLH genes have been correlated with severe COVID-19 symptomology and clinical outcomes [6]. Mutations in STXBP2 have been previously shown to cause pHLH via homozygous germline mutations [26].…”

“…In later onset sHLH, there is growing identification of heterozygous mutations, hypomorphic and partial or complete dominant-negatives, leading to a similar presentation as pHLH, but occurring later in life with a higher threshold for disease [5]. These perforin-mediated cytolytic pathway heterozygous pHLH gene mutations (e.g., PRF1, UNC13D, AP3B1) have been reported in some cases of severe COVID-19 with HLH features [6]. In this report, we present an 18year-old female with severe COVID-19 and features of HLH, who was found to have a rare (0.036%, Genome Aggregation Database) heterozygous STXBP2 (c.1286C > T, p.Ala429Val) missense mutation and defective NK cell killing.…”

SARS-CoV-2/COVID-19 and its relationship with NOD2 and ubiquitination

“…The etiology for the occurrence of autoimmune and autoinflammatory diseases following COVID-19 infection and vaccination is not fully understood. It may be multifactorial, including abnormal activation of immune system and host genetic factors [ 18 ]. In this article, we provide a comprehensive review of SARS-CoV-2/COVID-19 infection and its interrelationship with nucleotide-binding oligomerization domain containing 2 (NOD2) and ubiquitination.…”