Research Article Genetic Diagnosis of Charcot-Marie-Tooth Disease in a Population by Next-Generation Sequencing Helle Høyer, 1,2,3 Geir J. Braathen, 1,2,3 Øyvind L. Busk, 1 Øystein L. Holla, 1 Marit Svendsen, 1 Hilde T. Hilmarsen, 1 Linda Strand, 1 Camilla F. Skjelbred, 1 and Michael B. Russell 2,3 1 Section of Medical Genetics, Department of Laboratory Medicine, Telemark Hospital, 3710 Skien, Norway 2 Head and Neck Research Group, Research Centre, Akershus University Hospital, Lørenskog, Norway 3 Campus Akershus University Hospital, University of Oslo, Nordbyhagen, Norway Correspondence should be addressed to Helle Høyer; helle.hoyer@sthf.no Received 27 February 2014; Accepted 20 May 2014; Published 16 June 2014 Academic Editor: Asude Alpman Durmaz Copyright © 2014 Helle Høyer et al. his is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Charcot-Marie-Tooth (CMT) disease is the most prevalent inherited neuropathy. Today more than 40 CMT genes have been identiied. Diagnosing heterogeneous diseases by conventional Sanger sequencing is time consuming and expensive. hus, more eicient and less costly methods are needed in clinical diagnostics. We included a population based sample of 81 CMT families. Gene mutations had previously been identiied in 22 families; the remaining 59 families were analysed by next-generation sequencing. hirty-two CMT genes and 19 genes causing other inherited neuropathies were included in a custom panel. Variants were classiied into ive pathogenicity classes by genotype-phenotype correlations and bioinformatics tools. Gene mutations, classiied certainly or likely pathogenic, were identiied in 37 (46%) of the 81 families. Point mutations in known CMT genes were identiied in 21 families (26%), whereas four families (5%) had point mutations in other neuropathy genes, ARHGEF10, POLG, SETX, and SOD1. Eleven families (14%) carried the PMP22 duplication and one family carried a MPZ duplication (1%). Most mutations were identiied not only in known CMT genes but also in other neuropathy genes, emphasising that genetic analysis should not be restricted to CMT genes only. Next-generation sequencing is a cost-efective tool in diagnosis of CMT improving diagnostic precision and time eiciency. 1. Introduction Charcot-Marie-Tooth (CMT) is the most common inherited neuropathy, afecting 40 to 81 cases per 100,000 in the Norwegian general population [1, 2]. CMT is clinically, neurophysiologically, and genetically heterogeneous. he clinical classiication is based on age at onset, distribution of muscle weakness, sensory loss, walking diiculties, and foot deformities [3]. CMT is neurophysiologically subdivided into a demyelinating (CMT1) and axonal (CMT2) form depending on whether the median motor nerve conduction velocity (NCV) is below or above 38 m/s, respectively. A third form, intermediate CMT, has both demyelinating and axonal features and NCV between 25 and 45 m/s [2, 3]. he mode of inheritance is autosomal dominant, autoso- mal recessive, or X-linked [3]. At present more than 40 CMT genes have been identiied and there are several genes asso- ciated with related conditions [4–8]. Genetic heterogeneity and pleiotropic genes, that is, mutations in diferent genes, cause a similar phenotype and mutations in a single gene cause diferent phenotypes, which adds to the complexity of CMT [3, 6, 7]. Furthermore, sporadic cases of CMT are not uncommon due to autosomal recessive inheritance, reduced penetrance, late onset, small family size, and de novo mutations [2, 8, 9]. he duplication of PMP22 is the most common cause of CMT. he prevalence was ∼15% in two Norwegian studies and up to 40% in other selected populations [2, 9–13]. Otherwise, CMT is caused by point-mutations, with rare exception of non-PMP22 copy-number variations (CNVs) [14, 15]. Establishing a genetic CMT diagnosis provides patients and Hindawi Publishing Corporation BioMed Research International Volume 2014, Article ID 210401, 13 pages http://dx.doi.org/10.1155/2014/210401