Rare Variants of Immune-Related Genes Increase Susceptibility to Autoimmune Encephalitis: An Association Study

Autoimmune encephalitis (AE) is a neurological disorder caused by immune responses targeting neuron-surface or synaptic proteins. While its immunological mechanisms have been studied, the genetic underpinnings remain unclear. This study investigates whether rare deleterious variants (RDVs) in immunological genes contribute to AE susceptibility.

We enrolled 36 patients with AE and 407 healthy controls without autoimmune diseases. Whole-exome sequencing was performed to identify RDVs, including start-loss, stop-gain, frameshift, splice-site variants, and deleterious missense mutations. We analyzed the distribution of RDVs in an immunological gene set and its subsets. A burden test was used to identify genes significantly associated with AE.

Overall, RDVs in the full immunological gene set did not differ between AE patients and controls. However, the T cell receptor signaling pathway subset showed a significantly higher RDV burden in AE patients. Within this pathway, PDK1 was significantly associated with AE. Two additional genes, CAT and MIA, also showed strong associations, although their broader gene subset, cytokines, did not display differential RDV distribution.

Our findings suggest that RDVs in specific immunological pathways, particularly the T cell receptor signaling pathway, may play a role in AE pathogenesis. The significant associations of PDK1, CAT, and MIA with AE highlight potential genetic contributors to the disease. Further functional studies are necessary to validate these associations and explore their biological relevance, potentially paving the way for improved understanding and future therapeutic targets in AE.