title: Variants in the genes DCTN2, DNAH10, LRIG3, and MYO1A are associated with intermediate Charcot-Marie-Tooth disease in a Norwegian family.
abstract: BACKGROUND
  Charcot-Marie-Tooth disease (CMT) is a heterogeneous inherited neuropathy. The number of known CMT genes is rapidly increasing mainly due to next-generation sequencing technology, at present more than 70 CMT-associated genes are known. We investigated whether variants in the DCTN2 could cause CMT.
  
  
  METHODS
  Fifty-nine Norwegian CMT families from the general population with unknown genotype were tested by targeted next-generation sequencing (NGS) for variants in DCTN2 along with 32 CMT genes and 19 other genes causing other inherited neuropathies or neuronopathies, due to phenotypic overlap. In the family with the DCTN2 variant, exome sequencing was then carried out on all available eight family members to rule out the presence of more potential variants.
  
  
  RESULTS
  Targeted NGS identified in one family a variant of DCTN2, c.337C>T, segregating with the phenotype in five affected members, while it was not present in the three unaffected members. The DCTN2 variant c.337C>T; p.(His113Tyr) was neither found in in-house controls nor in SNP databases. Exome sequencing revealed a singular heterozygous shared haplotype containing four genes, DCTN2, DNAH10, LRIG3, and MYO1A, with novel sequence variants. The haplotype was shared by all the affected members, while the unaffected members did not have it.
  
  
  CONCLUSIONS
  This is the first time a haplotype on chromosome 12 containing sequence variants in the genes DCTN2, DNAH10, LRIG3, and MYO1A has been linked to an inherited neuropathy in humans.
authors.affiliation: Head and Neck Research Group, Research Centre, Akershus University Hospital, Lørenskog, Oslo, Norway.|Institute of Clinical Medicine, Campus Akershus University Hospital, University of Oslo, Nordbyhagen, Oslo, Norway.|Section of Medical Genetics, Department of Laboratory Medicine, Telemark Hospital, Skien, Norway.
authors.forename: G J
authors.initials: GJ
authors.lastname: Braathen
authors.affiliation: Head and Neck Research Group, Research Centre, Akershus University Hospital, Lørenskog, Oslo, Norway.|Institute of Clinical Medicine, Campus Akershus University Hospital, University of Oslo, Nordbyhagen, Oslo, Norway.|Section of Medical Genetics, Department of Laboratory Medicine, Telemark Hospital, Skien, Norway.
authors.forename: H
authors.initials: H
authors.lastname: Høyer
authors.affiliation: Section of Medical Genetics, Department of Laboratory Medicine, Telemark Hospital, Skien, Norway.
authors.forename: Ø L
authors.initials: ØL
authors.lastname: Busk
authors.affiliation: Section of Medical Genetics, Department of Laboratory Medicine, Telemark Hospital, Skien, Norway.
authors.forename: K
authors.initials: K
authors.lastname: Tveten
authors.affiliation: Section of Medical Genetics, Department of Laboratory Medicine, Telemark Hospital, Skien, Norway.
authors.forename: C F
authors.initials: CF
authors.lastname: Skjelbred
authors.affiliation: Head and Neck Research Group, Research Centre, Akershus University Hospital, Lørenskog, Oslo, Norway.|Institute of Clinical Medicine, Campus Akershus University Hospital, University of Oslo, Nordbyhagen, Oslo, Norway.
authors.forename: M B
authors.initials: MB
authors.lastname: Russell
mesh_terms: D056444:Axonemal Dyneins / Q000235:genetics*; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D000072159:Dynactin Complex / Q000235:genetics*; D005838:Genotype; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D018995:Myosin Heavy Chains / Q000235:genetics*; D024461:Myosin Type I / Q000235:genetics*; D009664:Norway
chemical_list: C000606361:DCTN2 protein, human; D000072159:Dynactin Complex; C496406:LRIG3 protein, human; C062291:MYO1A protein, human; D008565:Membrane Proteins; D024461:Myosin Type I; D018995:Myosin Heavy Chains; D056444:Axonemal Dyneins
keywords: Charcot-Marie-Tooth disease; DCTN2; exome sequencing; inherited neuropathy; targeted next-generation sequencing