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April 22, 2026Open Access

Genetic role in autoimmune encephalitis and paraneoplastic neurological syndromes

SBSophie N.M. Binks JYJeroan YipWarneford Hospital JKJulian C. KnightChinese Academy of Medical Sciences & Peking Union Medical College

Key Points

To review genetic factors involved in autoimmune encephalitis and paraneoplastic neurological syndromes and their implications for clinical management.
Synthesis of recent findings in genetic contributors to autoimmune encephalitis and paraneoplastic neurological syndromes.
Analysis of multiethnic studies linking specific genetic haplotypes to disease phenotypes.
Use of genome-wide association studies to identify risk loci associated with encephalitis.
Refined understanding of the HLA region's role in immune response involving T cell activity.
Identified specific genetic haplotypes linked to sensory neuropathy in anti-Hu positive paraneoplastic neurological syndromes.
Discovery of a risk locus in the gene PTPRD related to LGI1 antibody encephalitis.

Abstract

Purpose of review To synthesize evidence and recent advances concerning genetic contributors to autoimmune encephalitis (AE) and paraneoplastic neurological syndromes (PNS), relating these to disease processes and clinical management. Recent findings The known immunogenetic role of the human leucocyte antigen (HLA) region – critical to immune and infection response – was refined. A multiethnic IgLON5 study revealed DQ associations, surpassing those previously demonstrated with DR , and arguing for T cell involvement. In PNS with anti-Hu antibodies, a DQB1*02:01 ~ DRB1*03:01 haplotype was preferentially linked to a sensory neuropathy phenotype. Outside the HLA, there were genome-wide association studies (GWAS) in the two commonest AEs. The first AE GWAS with discovery and validation cohorts took place in leucine-rich glioma-inactivated 1-antibody encephalitis (LGI1-Ab-E). This identified a risk locus in PTPRD , a protein tyrosine phosphatase with dual immune and brain activity, and a polygenic risk score (PRS). In N -methyl- d -aspartate receptor-antibody encephalitis (NMDAR-Ab-E), a discovery-only cohort implicated the type 1 interferon pathway gene IFIH1. Summary Genetic status can perform as a biomarker or prioritize targets for drug development. The paucity of familial cases, the allele frequency of risk HLAs in healthy individuals, and the applicability of PRS, support a multihit model combining genetic and environmental risks.

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