title: Genetic diagnosis of Charcot-Marie-Tooth disease in a population by next-generation sequencing.
abstract: Charcot-Marie-Tooth (CMT) disease is the most prevalent inherited neuropathy. Today more than 40 CMT genes have been identified. Diagnosing heterogeneous diseases by conventional Sanger sequencing is time consuming and expensive. Thus, more efficient and less costly methods are needed in clinical diagnostics. We included a population based sample of 81 CMT families. Gene mutations had previously been identified in 22 families; the remaining 59 families were analysed by next-generation sequencing. Thirty-two CMT genes and 19 genes causing other inherited neuropathies were included in a custom panel. Variants were classified into five pathogenicity classes by genotype-phenotype correlations and bioinformatics tools. Gene mutations, classified certainly or likely pathogenic, were identified in 37 (46%) of the 81 families. Point mutations in known CMT genes were identified 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 identified 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-effective tool in diagnosis of CMT improving diagnostic precision and time efficiency.
authors.affiliation: Section of Medical Genetics, Department of Laboratory Medicine, Telemark Hospital, 3710 Skien, Norway ; Head and Neck Research Group, Research Centre, Akershus University Hospital, Lørenskog, Norway ; Campus Akershus University Hospital, University of Oslo, Nordbyhagen, Norway.
authors.forename: Helle
authors.initials: H
authors.lastname: Høyer
authors.affiliation: Section of Medical Genetics, Department of Laboratory Medicine, Telemark Hospital, 3710 Skien, Norway ; Head and Neck Research Group, Research Centre, Akershus University Hospital, Lørenskog, Norway ; Campus Akershus University Hospital, University of Oslo, Nordbyhagen, Norway.
authors.forename: Geir J
authors.initials: GJ
authors.lastname: Braathen
authors.affiliation: Section of Medical Genetics, Department of Laboratory Medicine, Telemark Hospital, 3710 Skien, Norway.
authors.forename: Øyvind L
authors.initials: ØL
authors.lastname: Busk
authors.affiliation: Section of Medical Genetics, Department of Laboratory Medicine, Telemark Hospital, 3710 Skien, Norway.
authors.forename: Øystein L
authors.initials: ØL
authors.lastname: Holla
authors.affiliation: Section of Medical Genetics, Department of Laboratory Medicine, Telemark Hospital, 3710 Skien, Norway.
authors.forename: Marit
authors.initials: M
authors.lastname: Svendsen
authors.affiliation: Section of Medical Genetics, Department of Laboratory Medicine, Telemark Hospital, 3710 Skien, Norway.
authors.forename: Hilde T
authors.initials: HT
authors.lastname: Hilmarsen
authors.affiliation: Section of Medical Genetics, Department of Laboratory Medicine, Telemark Hospital, 3710 Skien, Norway.
authors.forename: Linda
authors.initials: L
authors.lastname: Strand
authors.affiliation: Section of Medical Genetics, Department of Laboratory Medicine, Telemark Hospital, 3710 Skien, Norway.
authors.forename: Camilla F
authors.initials: CF
authors.lastname: Skjelbred
authors.affiliation: Head and Neck Research Group, Research Centre, Akershus University Hospital, Lørenskog, Norway ; Campus Akershus University Hospital, University of Oslo, Nordbyhagen, Norway.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Russell
mesh_terms: D002607:Charcot-Marie-Tooth Disease / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D056726:Genetic Association Studies; D005828:Genetics, Population; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009154:Mutation; D020641:Polymorphism, Single Nucleotide