Gain-of-function mutations in distinct ion channels cause diverse diseases including but not limited to: (NaV1.7) inherited erythromelalgia and paroxysmal extreme pain disorder (Waxman, 2013); (CaV2.1) familial hemiplegic migraine (Pietrobon, 2010); (CaV1.2) Timothy syndrome (Splawski et al., 2004); (TrpV4) heritable skeletal dysplasia (Rock et al., 2008); (KCNQ1 and HERG) short QT syndrome and familial atrial fibrillation (Giudicessi and Ackerman, 2012). Here, TRPV4 is linked to paroxysmal extreme pain disorder.