GenoMISC: Genetic Determinants of Multisystem Inflammatory Syndrome after SARS-CoV-2 Infection in Children (MIS-C)

Introduction: The clinical course of SARS-CoV-2 infection varies widely from patient to patient and is dependent on individual-level factors not yet fully characterized. In this study, we sought to identify individual-level factors affecting the clinical manifestation of Multisystem Inflammatory Syndrome in Children (MIS-C) after SARS-CoV-2 infection, a diffuse hyperinflammatory condition which can cause life-threatening cardiovascular impairment in a subset of SARS-CoV-2-infected children.

Objective: In this study, we sought to use whole genome sequencing and immunophenotyping to identify genetic determinants of the incidence and cardiovascular severity of MIS-C.

Methods: Genome sequencing was performed on 403 subjects from the Pediatric Heart Network's MUSIC (Long-TerM OUtcomes after the Multisystem Inflammatory Syndrome in Children) Study. Immunophenotyping of 20 MIS-C compared to COVID-exposed non-MIS-C subjects is being used to identify candidate biologic pathways involved in MIS-C. HLA genotyping and genetic variant burden in relevant biologic pathways is being used to identify genetic determinants of the risk of developing MIS-C and those that affect the severity of the cardiovascular manifestations. Two primary cardiovascular outcomes (i) ventricular function (left ventricular ejection fraction) and (ii) hypotension (presence of one or more of the following: need for multiple inotropes, cardiac arrest/ECMO or renal failure/dialysis) will be examined.

Results: To date, HLA genotyping on 403 MIS-C subjects has been compared to two different control cohorts of ~6,000 and 6,751 subjects. Using principal components and ancestries as covariates, there were several HLA markers with p-value <0.001, but none remained significant after Bonferroni correction. Immunophenotyping is progressing. Genome-wide damaging genetic variant identification has been performed on the MIS-C subjects and analyses are ongoing to assess variant burden in the relevant biologic pathways potentially impacting MIS-C incidence or severity.

Conclusion/Discussion: HLA haplotype does not have a strong influence on the likelihood of being diagnosed with MIS-C indicating that other genetic and environmental factors may have a greater role. Ongoing analyses will help determine which genetic pathways predispose to MIS-C and impact the severity of the cardiovascular manifestations. These findings will provide insight into MIS-C and, more generally, into other hyperinflammatory responses to novel infectious exposures.

Key Topics:

• Assay and in vitro studies to gain mechanistic insights
• Biomarker, in-depth phenotyping assays and in vitro studies using tissue and other biospecimens
• Developing models of similar diseases/syndrome