Primary Dysautonomia (PD) is a condition in which the autonomic nervous system does not function correctly leading to disabling and pervasive disease. To start investigating the pathogenesis of PD, we initiated a large-scale exome sequencing project consisting of an unprecedented pool of patients and identified mutations in voltage-gated sodium channels as clinically relevant. To probe the involvement of these genes in autonomic dysfunction and PD, we are creating robust animal models in which therapeutics can be tested, and by doing so, we expect to generate a first glimpse into possible causes of PD.