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. !
Peripheral neuropathies, also known as Charcot-Marie-Tooth disease (CMT) are inherited disorder peripheral nerve degeneration. More than half of all affected families with the more prevalent axonal type of CMT currently remain without a definite diagnosis, because the underlying genetic factors that cause their disease have not yet been identified. Our study aims to use whole genome sequencing and innovative expression studies to identify these unknown CMT genes. We will also take advantage of a multi ancestry set of families and cases from the CMT-International Database effort. This will ultimately allow to devise strategies to treat the disease.
