Retrospective analysis of NGS data in pediatric genetic cohort: detection of rare variants that may impact influenza and COVID-19 infection

ABSTRACT

It is difficult to assign a precise frequency of infections that defines an increased susceptibility to infections reflecting an impaired immune response given the majority of patients with intact immune systems still contract multiple upper respiratory infections each year, usually of viral origin. In fact, the average child may experience up to six to eight upper respiratory infections each year. The frequency of these infections may be related to environmental exposures but also may be triggered by genetic susceptibility. As an example, respiratory disease complicates the management of several inherited metabolic diseases, either at presentation or as late-onset features. More recently, children of all ages have been shown to contract COVID-19;however, children with underlying medical conditions are at increased risk. COVID-19 has been known for almost a year now, with several studies identifying genetic risk factors are associated with severe COVID-19. In the context of a health system wide genomic medicine program “Genomic Answers for Kids” at Children’s Mercy, Kansas City, we performed a retrospective analysis of rare variants predicted to be deleterious at 12 known loci known to govern TLR3- and IRF7- dependant type I Interferon immunity of all patients/families (>2000) tested for suspected genetic disorders. We bioinformatically extracted all rare variants in those 12 genes linked to type I interferon pathway from our internal warehouse. From those, ~340 variants were further analyzed based on inheritance, minor allele frequency in population datasets, and in silico prediction. The vast majority of this subgroup of GA4 K patients were referred for a suspected neurological disorder with or without multiple congenital anomalies (~75%). Only 15% were referred for metabolic disorders. Of those, 50% have a known genetic diagnosis unrelated to Immune deficiency. Of the selected index cases, the medical records, and if available the outpatient records, were reviewed to document the occurrence of recurrent infection and/or COVID-19. Preliminary data showed 46 “extremely” rare variants were detected in 37 GA4 K patients;6/37 (16%) have ≥2 in 1–12 genes, one GA4 K patient has 4 “extremely” rare variants in IRF7, and 3/37 GA4 K patients are deceased (~1%). Moreover, a novel disease gene was uncovered in a previously undiagnosed family, of which we identified an additional two affected individuals from an international collaboration. Finally, in a family with apparently dominant transmission of tumid lupus we observe putative causal variant in gene UNC93B1 – linking chronic inflammatory disorder (with known type I interferon association) to mutations predisposing to COVID-19. Recurrent or persistent infection is usually a manifestation of primary immunodeficiency. While most children with recurrent infections have a normal immunity, it is important to remember a subset of patients have an unrecognized genetic susceptibility to infection. Further analysis and monitoring are on-going. As we are continuing to struggle with the COVID-19 pandemic, combined with flu season, understanding precisely who may be at higher risk of infection and complications is critical and could play an important role in ongoing efforts to in disease prevention and the development of better treatment protocols