Exome Sequencing Implicates Impaired GABA Signaling and Neuronal Ion Transport in Trigeminal Neuralgia

Weilai Dong, Sheng Chih Jin, August Allocco, Xue Zeng, Amar H. Sheth, Shreyas Panchagnula, Annie Castonguay, Louis Étienne Lorenzo, Barira Islam, Geneviève Brindle, Karine Bachand, Jamie Hu, Agata Sularz, Jonathan Gaillard, Jungmin Choi, Ashley Dunbar, Carol Nelson-Williams, Emre Kiziltug, Charuta Gavankar Furey, Sierra ConinePhan Q. Duy, Adam J. Kundishora, Erin Loring, Boyang Li, Qiongshi Lu, Geyu Zhou, Wei Liu, Xinyue Li, Michael C. Sierant, Shrikant Mane, Christopher Castaldi, Francesc López-Giráldez, James R. Knight, Raymond F. Sekula, J. Marc Simard, Emad N. Eskandar, Christopher Gottschalk, Jennifer Moliterno, Murat Günel, Jason L. Gerrard, Sulayman Dib-Hajj, Stephen G. Waxman, Fred G. Barker, Seth L. Alper, Mohamed Chahine, Shozeb Haider, Yves De Koninck, Richard P. Lifton, Kristopher T. Kahle

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)


Trigeminal 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-associated de novo mutation (p.Cys188Trp) in the GABAA receptor Cl channel y-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 thea-1H subunit of the voltage-gatedCa2+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.
Original languageEnglish
Article number101552
Number of pages26
Issue number10
Early online date11 Sep 2020
Publication statusPublished - 23 Oct 2020
Externally publishedYes


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