Objectives: To describe the clinical and electrophysiologic features of synaptotagmin II (SYT2) mutations, a novel neuromuscular syndrome characterized by foot deformities and fatigable ocular and lower limb weakness, and the response to modulators of acetylcholine release. Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders caused by abnormal signal transmission between motor axons and skeletal muscle. Methods:1 Mutations in an increasing number of presynaptic proteins, components of the synaptic basal lamina, proteins involved in endplate development and maintenance, and more recently in protein glycosylation 2 have been reported, causing novel and complex phenotypes. Since most CMS are treatable, diagnosing them is of utmost importance.Signal transmission at the neuromuscular junction is mediated via the release of acetylcholine from synaptic vesicles.3 This process is rendered calcium sensitive by members of the synaptotagmin protein family, which also have a role in vesicle priming and in reducing spontaneous transmitter release.4,5 Synaptotagmin II (SYT2) is the major isoform expressed at the neuromuscular junction, and Syt2 knockout mice show markedly reduced calcium-evoked transmitter release.6 Synaptotagmins interact with SNAP-25, 5 and mutations in SNAP25B have been described in patients with myasthenia and additional CNS phenotypes. Herein, we describe the clinical and electrophysiologic characteristics of 2 multigenerational families displaying a novel human motor syndrome caused by dominant SYT2 mutations: c.920T.G