摘要：SummaryTrigeminal neuralgia (TN) is a common, debilitating neuropathic face pain syndrome often resistant to therapy. The familial clustering of TN cases suggests that genetic factors play a role in disease pathogenesis. However, no unbiased, large-scale genomic study of TN has been performed to date. Analysis of 290 whole exome-sequenced TN probands, including 20 multiplex kindreds and 70 parent-offspring trios, revealed enrichment of rare, damaging variants in GABA receptor-binding genes in cases. Mice engineered with a TN-associatedde novomutation (p.Cys188Trp) in the GABAAreceptor Cl−channel γ-1 subunit (GABRG1) exhibited trigeminal mechanical allodynia and face pain behavior. Other TN probands harbored rare damaging variants in Na+and Ca+channels, including a significant variant burden in the α-1H subunit of the voltage-gated Ca2+channel Cav3.2 (CACNA1H). These results provide exome-level insight into TN and implicate genetically encoded impairment of GABA signaling and neuronal ion transport in TN pathogenesis.Graphical AbstractDisplay OmittedHighlights•Genomic analysis of trigeminal neuralgia (TN) using exome sequencing•Rare mutations in GABA signaling and ion transport genes are enriched in TN cases•Generation of a genetic TN mouse model engineered with a patient-specific mutationNeuroscience; Structural Biology; Genomics
