IDENTIFYING GENETIC FACTORS THAT CAUSE AND MODIFY CMT More than 80 different genes have been identified to cause the various forms of CMT. For the demyelinating forms of CMT, a genetic cause can be found most of the time, with CMT1A (PMP22 duplication) explaining ~70% of these cases. In contrast, a mutation in one of the currently known genes can be found in less than 40% of axonal (CMT2) cases, mostly for the severe, early onset cases. Genetic studies have fundamentally transformed our knowledge on CMT and have catalyzed much of the research in neuropathies in the past 20 years. We fully expect that by taking advantage of new technologies, this progress will continue to a point where (1) >90% of CMT1 and CMT2 patients can receive a genetic diagnosis; (2) a sizable number of important genetic modifiers that account for a significant portion of the phenotypic variability in some forms of CMT will be identified; (3) a proportion of the heretofore idiopathic/sporadic neuropathies will be found to have a genetic cause; (4) genetic risk factors for developing neuropathy to diabetes and various medications will be identified. The members of the INC consortium work in a collaborative manner with multiple sources of funding to achieve these goals. In particular, the INC has allowed us to collect high-quality samples for novel gene identification (15 new CMT genes) and also for reliable gene modifier studies, as demonstrated by our results in a CMT1A study. In this renewal, we propose to expand our efforts to find new genes that cause CMT and genetic modifiers of CMT. Novel genes will expand our understanding of pathogenic mechanisms and demyelination. They will also provide new therapeutic targets. Modifiers will also be important targets for intervention, and may well be important in the manifestations of acquired peripheral neuropathies, and even other diseases, such as amyotrophic lateral sclerosis (ALS) and multiple sclerosis, in which axonal degeneration has been implicated in the pathogenesis. Finally, as our collaborative group and others move rapidly towards genomic approaches, we will establish a unified, secure, and accessible resource for all genomic data of the INC that will be open to all CMT and other genetic researchers, that can also serve as a blueprint for other RDCRN groups interested in inherited diseases.
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