The total number of currently known rare diseases has been estimated to be >10,000, resulting in a population prevalence of ~5%. With the advent of next-generation sequencing (NGS), the last decade has witnessed an exponential increase in the identification of novel disease genes. More than 250 gene discoveries are being made annually and it is estimated that as many as 10,000 additional genes associated with Mendelian disease remain to be detected. Neurologic disorders are the leading cause of disability and the second leading cause of death. In this research proposal, gene discovery efforts will be focused on adult-onset neurological/neurodegenerative disorders. We will explore the vast uncharted territory of unidentified ultrarare neurological disorders by combining (1) multi-disciplinary rare disease diagnostics, (2) international networking/data sharing, (3) NGS-based technologies and (4) functional studies (multi-omics, epigenetics and small organism modeling).