Clinical Characteristics And Next-generation Sequencing Analysis Of Familial Trigeminal Neuralgia Patients

Background: Trigeminal neuralgia(TN)is a common and serious chronic neuropathic degenerative pain disorder.The pathogenesis of trigeminal neuralgia is still unclear.TN with familial clustering(≥ 2 TN patients in one kindred family)is called familial trigeminal neuralgia(FTN),which may be associated with inherited genetic factors according to previous literature.While new genetic analysis methods are widely used in the clinic,few researchers have focused on FTN.This study investigated the pathogenic mechanism of FTN by using next-generation sequencing technology,which may enhance our understanding of human TN pathophysiology.Method: We performed whole-exome sequencing(WES)for 7 probands from families of FTN.Sanger sequencing was performed for two control groups(FTN family members group and nonfamilial TN subject group)to potentially identify new FTN-related gene mutations.In families where FTN probands carried potentially pathogenic gene mutations,the ribonucleic acid(RNA)of FTN probands and related family members group(control group 1,G1),as well as nonfamilial TN patients(control group 2,G2)were analysed by RNA sequencing(RNA-seq)to confirm differential gene expression.Results: Seven probands were derived from 3 Chinese families.WES and Sanger sequencing identified MARS1 mutation c.2398C>A p.(Pro800Thr)in Family 1.MARS1 mutation was confirmed in 14/26 [53.8%] members of Family 1 in FTN family member group,while none of nonfamilial TN subjects had this MARS1 mutation.RNA-seq showed that 3probands in Family 1 had higher expression of Fosl1(Fos-like antigen 1)and NFE2(Nuclear factor,erythroid 2)than 3 subjects in the nonfamilial TN subject group.Fosl1 and NFE2 are genes related to integrated stress response(ISR).Conclusion: MARS1 mutations may cause chronic activation of ISR,contribute to ISR pathophysiological changes in FTN,and cause/accelerate peripheral nerve degeneration.The findings of this study can enrich our knowledge of the role of molecular genetics in TN in humans.