# Single gene inborn errors of immunity underlying SARS-CoV-2-related multisystem inflammatory syndrome in children: a new approach to tackle a seemingly old puzzle

> **NIH NIH R21** · ROCKEFELLER UNIVERSITY · 2022 · $254,250

## Abstract

Project Summary
A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been quickly
spreading around the world since December 2019 and causing coronavirus disease 2019 (COVID-19) in
populations naive to this new pathogen. Since early May 2020, a rare and life-threatening SARS-CoV-2-related
Kawasaki-like disease, designated by the CDC as Multisystem Inflammatory Syndrome in Children (MIS-C),
emerged in communities with high rates of COVID-19. Clinical and laboratory characteristics of patients have
revealed multiple similarities between MIS-C and Kawasaki disease (KD), a well-known but poorly understood
pediatric inflammatory condition. The past ~50 years of studies on KD suggest that infectious agents, including
a variety of viruses in particular, can trigger an inflammatory cascade that drives the clinical manifestations in
genetically vulnerable children. However, the genetic etiologies and immunological mechanisms of KD remain
largely unknown. The emergence of MIS-C during the COVID-19 epidemic provides compelling evidence of a
viral trigger, at least for this specific form of Kawasaki-like disease. We and others have previously identified a
number of monogenic inborn errors of immunity (IEIs) underlying a variety of severe viral diseases. We now aim
to dissect the immunopathogenesis of MIS-C by testing a monogenic hypothesis. We will recruit a cohort of at
least 1,000 MIS-C patients, by utilizing the COVID Human Genetic Effort (www.covidhge.com), our global
network of pediatricians, and the New York State Department of Health (NYSDOH). We will perform whole
exome sequencing (WES) and whole genome sequencing (WGS) sequentially for all enrolled patients. We will
search for rare single gene IEIs underlying MIS-C via an unbiased genome-wide approach, by analyzing the
WES and WGS data at the cohort population (genetic homogeneity) and individual patient levels (genetic
heterogeneity), also testing models of immunological homogeneity and heterogeneity. For all candidate MIS-C-
causing genes, we will perform in-depth characterization at the molecular and cellular levels, to connect the
candidate genotype to molecular mechanism(s) and cellular phenotype(s) relevant to the MIS-C pathogenesis.
We will use patient-specific leukocytes, dermal fibroblasts, and human pluripotent stem cell (hPSC)-derived MIS-
C disease-relevant cell types, such as cardiovascular endothelial cells or cardiomyocytes. Our preliminary data
are encouraging, as we have already enrolled 812 patients and performed WES on 620 of them. For comparison,
we have also enrolled 158 patients with classic KD and have sequenced all of them. This project focuses on a
timely and devastating problem, tests a bold but plausible hypothesis, and takes advantage of cutting-edge
genetic and mechanistic approaches. It will enable us to gain insight into the molecular and cellular basis of the
immunopathology of SARS-CoV-2-related MIS-C in previously healthy children an...

## Key facts

- **NIH application ID:** 10453277
- **Project number:** 1R21AI160576-01A1
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Shen-Ying Zhang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $254,250
- **Award type:** 1
- **Project period:** 2022-05-20 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10453277

## Citation

> US National Institutes of Health, RePORTER application 10453277, Single gene inborn errors of immunity underlying SARS-CoV-2-related multisystem inflammatory syndrome in children: a new approach to tackle a seemingly old puzzle (1R21AI160576-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10453277. Licensed CC0.

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