NEW YORK – Researchers at Children's Mercy Research Institute have been investigating rare genetic variants in a growing pediatric patient cohort in an effort to understand susceptibility to severe COVID-19 or other viral infections.
In a presentation at the American College of Medical Genetics and Genomics annual clinical meeting on Thursday, Isabelle Thiffault, director of translational genetics at Children's Mercy and a researcher with the University of Missouri at Kansas City, 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.
The GA4K team ultimately plans to collect a wide range of molecular data types for the cohort, Thiffault noted, 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.
With the onset of the COVID-19 pandemic last spring, the researchers initially decided to tap into already available molecular and clinical data for more than 2,000 families enrolled in GA4K to search for rare SNPs, haplotypes, and structural variants in 13 type I interferon genes implicated in large adult studies of severe COVID-19. They also reviewed medical records to document relevant infections with SARS-CoV-2 or other viruses.
When the investigators focused on TLR3- and IRF7-dependent type I interferon immunity genes, they 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.
By digging into gene annotation profiles and available clinical data for patients with the rare variants, the team saw potential ties to several conditions, including a form of neurodevelopmental disorder marked by both recurrent respiratory infections and respiratory syncytial virus susceptibility in infancy.
The team is now turning to functional studies and other approaches to dig into the rare variant set identified in the initial analysis, and to search for firmer associations between these changes and pediatric risk of severe viral disease, including COVID-19.
"Because most children with COVID-19 have mild or no symptoms, is it almost impossible to create the scores of severely affected and mild [infections] and to look at the genotype," she explained. "We believe that identifying those patients with risk factors — and also, maybe, genetic predisposition to severe viral infection — may contribute to [an understanding of] the natural history of COVID-19 disease."
Thiffault cautioned that a significant proportion of severe COVID-19 cases cannot be explained by the genes and pathways identified so far, and emphasized the importance of considering the role that health disparities and other contributors may play.
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 US children diagnosed with MIS-C before early March of this year, some 60 percent were male and more than 65 percent came from Hispanic/Latino or African American groups, according to data from the US Centers for Disease Control and Prevention Thiffault presented.
Studies like these are expected to prove beneficial beyond COVID-19, since as many as 200 viruses are believed to cause respiratory infections, Thiffault explained. 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 investigators are continuing to search for additional variants that may impact COVID-19 susceptibility, she said, and plan to collect additional data to try to find factors that can impact viral infections in children more broadly.