Inborn Errors of OAS–RNase L in SARS-CoV-2–related Multisystem Inflammatory Syndrome in Children

Children infrequently have severe consequences of severe acute respiratory syndrome coronavirus 2 infection. As a general hypothesis, any who do must either have some predisposing condition or genetic susceptibility. Although some children have had severe coronavirus 2019 (COVID) pneumonia and acute illness, it was discovered in 2020 that some present around four weeks after infection with an inflammatory illness having some similarity to Kawasaki disease.

This condition was named multisystem inflammatory disease in children (MIS-C) and affects 1 in 10 000 children infected with severe acute respiratory syndrome coronavirus 2. Much has been learned about MIS-C over the past few years and this study is a genetic evaluation of a multinational cohort of MIS-C patients trying to identify over-represented genetic variants that could be causative.

An international collaborative, the COVID Human Genetic Effort cohort had collected 558 patients with MIS-C that were subject to whole-exome or whole-genome sequencing.

Within the MIS-C sequences obtained for this effort homozygous or hemizygous variants that were rare and predicted to abrogate gene function were sought.

Within that list, genes known to be relevant to viral immunity were identified and then checked to see if they were specific to the MIS-C cohort. Functionally, tests of the gene variants were performed in a variety of experimental cell systems and then the identified pathways confirmed as defective in patient cells.

Five MIS-C patients were identified having rare damaging variants in an autosomal recessive configuration in the 2′-5′-oligoadenylate synthetase (OAS) 1, 2 or ribonuclease L (RNase L) genes. One patient with biallelic OAS1, three with OAS2, and one with RNase L were ultimately found. These abnormalities were not found in the over 1000 patients with mild or asymptomatic COVID in the larger cohort and their incidence in the general population was exceedingly rare. Normally, the OAS proteins sense double-stranded RNA characteristic of viruses. They in turn activate RNase L, which degrades single stranded RNA. In a variety of experiments to test the variants found in the patients as well as the relevance of the pathway overall, it was identified that when defective it induces excessive cellular inflammatory responses in response to viral RNA. Interestingly, this was found most notably and selectively in mononuclear phagocytes. Clinically, all of the patients had Kawasaki-like disease and without COVID pneumonia and all recovered from MIS-C.

MIS-C is a disease of excessive cell- and tissue-specific inflammation in response to viral infection. One percent of an international cohort of MIS-C patients had genetic abnormalities of OAS or RNAase L pathways. The cell type specific impact of these variants in mononuclear phagocytes helps understand some of the specific attributes of MIS-C, such as the activation and expansion of CD4+ and CD8+ T cells. Importantly, the genes defining susceptibility to MIS-C are distinct from those leading to severe primary COVID which are those broadly affecting type-I interferon immunity.

MIS-C is an unusual consequence of having had COVID in childhood and has few parallels in clinical medicine. The most similar has been Kawasaki disease, which has been mechanistically puzzling for decades. This study gives tremendous insight into how MIS-C can happen as well as what should be considered in finally understanding Kawasaki disease and other perplexing conditions. Most notably that cell-type specific inherent inability to control viral sensing and resulting inflammatory pathways have the potential to result in very specific clinical sequelae. As a whole, this study defines the power of genomics in rare and confusing clinical presentations and should embolden collaboratives to take on these questions. Given that over 500 individuals were studied to obtain this mechanistically insightful 1% answer, it almost proves that such collaboratives are needed. Future products from this particular collaborative will undoubtedly provide deeper insight into MIS-C, COVID, and other clinically vexing atypical responses to viral infections.