PROJECT SUMMARY The various forms of Charcot-Marie-Tooth disease (CMT) comprise a genetically heterogeneous set of peripheral neuropathies. Currently >90 different CMT genes have been identified; yet, for the axonal CMT2 subtype these genes explain only 30-40% of the genetic effect. Especially the application of exome sequencing has led to an unprecedented pace in identifying about half of those genes in the past five years. We have been at the forefront of this development with 22+ published new gene identifications in the past seven years. This success was only possible through broad national and international collaborations, data sharing, and the development of advanced analysis tools and methods. We also learned that despite exome sequencing, over 50% of axonal CMT patients remain undiagnosed pointing towards even more genes; however, our preliminary data also support the existence of non- coding variation as Mendelian allele contributor. In this grant we will continue our highly impactful work in CMT family recruitment, exome sequencing and traditional gene identification. In addition, we will expand the genetic studies to whole genome sequencing with a focus on families already explored unsuccessfully in whole exome studies. We further plan to perform the first large rare variant burden analysis in the rare disorder CMT2 – this is only possibly through the exceptional clinical resources we have built over the past decade. Finally, with many CMT genes available, we will perform statistical network analyses on a CMT-ome to identify gene modules and pathways that will be the starting point of polypharmacology and provide insight into pathophysiology of peripheral nerve degeneration. All data will be available in real-time to an existing network of CMT investigators worldwide, and deposited in dbGAP annually. !