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Genetics of Charcot-Marie-Tooth (CMT) Disease within the Frame of the Human Genome Project Success
Peripheral Neuropathy Group, Molecular Genetics Department, VIB, University of Antwerp, Universiteitsplein 1, Antwerpen B2610, Belgium
Neurogenetics Group, Institute Born Bunge, University of Antwerp, Antwerpen B2610, Belgium
Department of Human Genetics, Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Biomedical Research Building, Room 523, LC: M-860, 1501 NW 10 Ave., Miami, FL 33136, USA
* Authors to whom correspondence should be addressed.
Received: 20 November 2013; in revised form: 8 January 2014 / Accepted: 10 January 2014 / Published: 22 January 2014
Abstract: Charcot-Marie-Tooth (CMT) neuropathies comprise a group of monogenic disorders affecting the peripheral nervous system. CMT is characterized by a clinically and genetically heterogeneous group of neuropathies, involving all types of Mendelian inheritance patterns. Over 1,000 different mutations have been discovered in 80 disease-associated genes. Genetic research of CMT has pioneered the discovery of genomic disorders and aided in understanding the effects of copy number variation and the mechanisms of genomic rearrangements. CMT genetic study also unraveled common pathomechanisms for peripheral nerve degeneration, elucidated gene networks, and initiated the development of therapeutic approaches. The reference genome, which became available thanks to the Human Genome Project, and the development of next generation sequencing tools, considerably accelerated gene and mutation discoveries. In fact, the first clinical whole genome sequence was reported in a patient with CMT. Here we review the history of CMT gene discoveries, starting with technologies from the early days in human genetics through the high-throughput application of modern DNA analyses. We highlight the most relevant examples of CMT genes and mutation mechanisms, some of which provide promising treatment strategies. Finally, we propose future initiatives to accelerate diagnosis of CMT patients through new ways of sharing large datasets and genetic variants, and at ever diminishing costs.
Keywords: Charcot-Marie-Tooth; peripheral neuropathy; genomic disorders; gene discoveries; next generation sequencing
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Timmerman, V.; Strickland, A.V.; Züchner, S. Genetics of Charcot-Marie-Tooth (CMT) Disease within the Frame of the Human Genome Project Success. Genes 2014, 5, 13-32.
Timmerman V, Strickland AV, Züchner S. Genetics of Charcot-Marie-Tooth (CMT) Disease within the Frame of the Human Genome Project Success. Genes. 2014; 5(1):13-32.
Timmerman, Vincent; Strickland, Alleene V.; Züchner, Stephan. 2014. "Genetics of Charcot-Marie-Tooth (CMT) Disease within the Frame of the Human Genome Project Success." Genes 5, no. 1: 13-32.