title: Clinical implications of genetic advances in Charcot-Marie-Tooth disease.
abstract: Charcot-Marie-Tooth disease (CMT) refers to a group of inherited neuropathies with a broad range of phenotypes, inheritance patterns and causative genes. The number of disease genes identified in CMT has expanded rapidly over the past few decades, such that more than 60 CMT-associated genes have now been discovered. This rise in genetic discovery can be attributed to the development of next-generation sequencing (NGS) technology, which allows the entire exome or genome to be sequenced in a matter of days. In this Review, we discuss how NGS is being employed in the diagnostic evaluation of patients with CMT and how the genetic advances in CMT are influencing clinical practice. In particular, we explore how genetic advances have broadened the phenotype of CMT and related disorders and how NGS allows a large number of CMT genes to be screened simultaneously early in the evaluation of an unexplained neuropathy. Finally, we discuss the different methods of NGS that can be used in CMT and related disorders, and propose a simple diagnostic algorithm in which clinical assessment and neurophysiology are used to guide the application of phenotype specific 'panels'.
authors.affiliation: MRC Centre for Neuromuscular Diseases, The National Hospital for Neurology and Neurosurgery and Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Rossor
authors.forename: James M
authors.initials: JM
authors.lastname: Polke
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
authors.forename: Mary M
authors.initials: MM
authors.lastname: Reilly
mesh_terms: D002607:Charcot-Marie-Tooth Disease / Q000175:diagnosis / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D017422:Sequence Analysis, DNA / Q000379:methods*
references.citation: Brain. 2006 Feb;129(Pt 2):411-25
references.pmid: 16364956
references.citation: Muscle Nerve. 2013 Jun;47(6):922-4
references.pmid: 23553728
references.citation: Dev Med Child Neurol. 2010 May;52(5):405-6
references.pmid: 20525039
references.citation: Nucleic Acids Res. 2002 Jun 15;30(12):e57
references.pmid: 12060695
references.citation: J Peripher Nerv Syst. 2011 Mar;16(1):1-14
references.pmid: 21504497
references.citation: N Engl J Med. 2010 Apr 1;362(13):1181-91
references.pmid: 20220177
references.citation: J Clin Invest. 2011 Dec;121(12):4735-45
references.pmid: 22045570
references.citation: Ann Neurol. 2011 Jan;69(1):22-33
references.pmid: 21280073
references.citation: J Genet Hum. 1978 Dec;26(4):311-49
references.pmid: 752065
references.citation: J Neurol Neurosurg Psychiatry. 2009 Jun;80(6):699-700
references.pmid: 19448103
references.citation: Nat Med. 2011 Jul 24;17(8):968-74
references.pmid: 21785432
references.citation: Neurology. 2012 Jul 10;79(2):192-4
references.pmid: 22675077
references.citation: Neurology. 2004 Mar 9;62(5):783
references.pmid: 15007131
references.citation: Nat Genet. 2011 Jun;43(6):595-600
references.pmid: 21532572
references.citation: Neuromuscul Disord. 2013 May;23(5):399-403
references.pmid: 23489662
references.citation: Clin Genet. 2013 Mar;83(3):221-31
references.pmid: 22642570
references.citation: Nat Med. 2004 Apr;10(4):396-401
references.pmid: 15034573
references.citation: Lancet Neurol. 2009 Jun;8(6):537-44
references.pmid: 19427269
references.citation: J Peripher Nerv Syst. 2012 May;17 Suppl 2:43-9
references.pmid: 22548623
references.citation: Neurology. 2008 Nov 18;71(21):1660-8
references.pmid: 18832141
references.citation: Rinsho Shinkeigaku. 2008 Jun;48(6):419-21
references.pmid: 18616154
references.citation: Nat Med. 2003 Dec;9(12):1533-7
references.pmid: 14608378
references.citation: Lancet Neurol. 2009 Dec;8(12):1103-10
references.pmid: 19818690
references.citation: Lancet Neurol. 2011 Apr;10(4):320-8
references.pmid: 21393063
references.citation: J Neurol Neurosurg Psychiatry. 2012 Jul;83(7):706-10
references.pmid: 22577229
references.citation: Neurology. 2012 Sep 11;79(11):1145-54
references.pmid: 22933740
references.citation: Neuromuscul Disord. 2009 Apr;19(4):264-9
references.pmid: 19272779
references.citation: Brain. 2012 Dec;135(Pt 12):3551-66
references.pmid: 23250879
references.citation: Neuromuscul Disord. 1991;1(2):93-7
references.pmid: 1822787
references.citation: J Neurol. 2012 Aug;259(8):1673-85
references.pmid: 22302274
references.citation: Nat Rev Genet. 2013 Apr;14(4):295-300
references.pmid: 23478348