Genetic Factors Linked to Severe COVID-19, Viral Infections in Children

Although children, in general, are thought to experience relatively mild infections with SARS-CoV-2, a subset of infected children do become very ill and develop a condition known as Multisystem Inflammatory Syndrome in Children (MIS-C).

As in adults, severe pediatric COVID-19 cases have been documented more frequently in children with conditions such as asthma, chronic lung disease, diabetes, immunosuppression, or other high-risk traits or conditions. Of more than 2,600 children in the USA diagnosed with MIS-C before early March of this year, some 60% were male and more than 65% came from Hispanic/Latino or African American groups.


A team of medical scientists working with the Children's Mercy Research Institute (Kansas City, MO, USA) investigated rare genetic variants in a growing pediatric patient cohort in an effort to understand susceptibility to severe COVID-19 or other viral infections. The team shared findings from a retrospective genomic analysis on data from the Genomic Answers for Kids (GA4K), an ongoing pediatric repository that plans to enroll some 30,000 children and their family members in the coming seven years. They collected a wide range of molecular data types for the cohort, including exome sequencing, short-read PCR-free genome sequencing, whole-genome bisulfite sequencing, single-cell genomic analyses, 10x Genomics linked read mapping, and long-read sequence data.

The investigators focused on TLR3- and IRF7-dependent type I interferon immunity genes, and identified nearly four dozen extremely rare variants in 37 GA4K participants, including three deceased patients and one individual who was carrying four very rare variants in the IRF7 gene. Around half of those patients had a history of recurrent infections, though the children had not been diagnosed with SARS-CoV-2 infections. The variants did not appear to be enriched in any one gene, and did not track with biological sex, metabolic phenotype, or with cases from the GA4K diagnostic cohort.

Isabelle Thiffault, PhD, the director of Translational Genetics and a co-author of the study, said, “Studies like these are expected to prove beneficial beyond COVID-19, since as many as 200 viruses are believed to cause respiratory infections. In a typical year, the average school age child experiences between six and 12 such infections, with acute respiratory infections accounting for up to one-fifth of acute hospital admissions in children.” The study was presented at the American College of Medical Genetics and Genomics annual clinical meeting held virtually between 13-16 April, 2021.


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Children's Mercy Research Institute