Biallelic Variants in OAS2 with Neurodevelopmental Disorders, Skeletal Dysplasia, and Immunodeficiency

Background/Purpose: Autophagy is an intracellular clearance mechanism for the degradation of deficient cellular cargo. Selective autophagy ensures the degradation of specific substrates, e.g., clearance of foreign germs (xenophagy). In normal health, xenophagy is increased via the RNaseL pathway by 2′,5′-oligoadenylate synthetase proteins (OAS) which are activated upon intracellular sensing of viral RNA. Recently, variants in the RNaseL pathway were annotated with SARS-CoV-2-related multisystem inflammatory syndrome in children (MISC) without developmental disorders. Here, we describe novel congenital OAS2-related disorders with a distinct developmental phenotype.

Methods: We present clinical, molecular, neuropathological, and imaging data of 4 patients from 3 families with biallelic variants in OAS2. These data are complemented by experimental findings from cellular assays and proteomics from human fibroblasts, as well as single cell RNA sequencing from peripheral blood mononuclear cells.

Results: We identified 4 patients from 3 families with recessive variants in OAS2 with skeletal dysplasia, variable neurodevelopmental disorders, and signs of immunodeficiency. Brain MRI revealed corpus callosum dysgenesis and histopathological examination showed damaged peripheral cutaneous nerve fibers. Cellular assays using patient fibroblasts revealed reduced OAS2 expression even after interferon stimulation and stalled autophagy with p62 accumulation. Proteomic analyses showed significant dysregulation of the RNaseL/OAS pathway and autophagy in patient fibroblasts. Single cell RNA sequencing showed defects in CD4+ T cells, monocytes, and B cells in patient peripheral blood mononuclear cells.

Conclusion: Our findings indicate biallelic OAS2 variants as a novel candidate gene for distinct developmental disorders due to deficient innate immune response and suggest close clinical and molecular links with deficient autophagy in an emerging group of monogenic neuroimmunological disorders.

Publication History

Article published online:
13 November 2023