Gene burden meta-analysis of 748 879 individuals identifies LGI1-ADAM23 protein complex association with epilepsy.

Rare coding variants in LGI1 and ADAM23 (synaptosomal protein complex) associated with epilepsy risk in mild and late-onset forms

This gene burden meta-analysis includes 748,879 individuals from UK Biobank, All of Us, and MGH Biobank, including 20,026 epilepsy cases. Rare variant burden testing identifies LGI1 as a significant association (a known familial epilepsy gene). Among the top 10 associated genes, ADAM23 — a partner of the LGI1 complex — emerges as a new candidate gene with first statistical evidence, supported by prior biological data in animal models.

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The statistical power of this biobank meta-analysis is remarkable: it enables identification of associations in mild and late-onset epilepsy, typically under-represented in clinical cohorts. The emergence of ADAM23 as a candidate gene paves the way for diagnostic testing targeting the LGI1-ADAM23 complex in unsolved epilepsies.

Clinical impact: 2/3 · Evidence strength: 3/3 · Novelty: 2/2 · Sample size: 1/1 · Publication status: 0/1 → Total: 8/10