PROJECT SUMMARY Primary Dysautonomia (PD), distinct from the entity called familial dysautonomia, is a multifactorial condition that runs in families in which the autonomic nervous system (ANS) does not function correctly leading to a range of disabling disease symptoms. Despite the known fact that PD exhibits Mendelian inheritance patterns, underlying genetic origins have not been identified. Treatments are solely based on alleviating symptomatology and there is no rationale for effectuating a cure. To help fill this knowledge gap and start identifying contributing factors to PD, we closely followed sixty-nine families with a dominant Mendelian inheritance pattern of multiple shared symptoms including (i) chronic orthostatic intolerance, (ii) chronic fatigue, (iii) primary focal hyperhidrosis, (iv) chronic itch, and (v) generalized anxiety. We initiated whole-exome sequencing (WES) of the probands in these families with resulting data suggesting a causal relationship between PD and an autosomal dominant inheritance pattern of mutations in genes encoding voltage-gated sodium (NaV) channels. This outcome is strengthened by the fact that we have treated family members with NaV channel modulators which resolved many of their complaints. Based on preliminary results, we hypothesize that what appears to pathophysiologically link diffuse autonomic symptoms, is a disease model in which NaV channel mutations can transform the ANS into an oversensitive nervous system that over time develops incapacitating and persistent disease. To start investigating the involvement of NaV channel mutations in PD, we devised a strategy to help elucidate the link between our targets and anomalous activation of the sympathetic nervous system in patients. Our approach will culminate in the creation of a validated animal model with autonomic dysfunction in which human therapeutics can be tested. Successful completion will provide new insights into genetic causes of PD, a vital step towards understanding the multifactorial nature of this disorder.