title: Whole Genome Sequencing Identifies a 78 kb Insertion from Chromosome 8 as the Cause of Charcot-Marie-Tooth Neuropathy CMTX3.
abstract: With the advent of whole exome sequencing, cases where no pathogenic coding mutations can be found are increasingly being observed in many diseases. In two large, distantly-related families that mapped to the Charcot-Marie-Tooth neuropathy CMTX3 locus at chromosome Xq26.3-q27.3, all coding mutations were excluded. Using whole genome sequencing we found a large DNA interchromosomal insertion within the CMTX3 locus. The 78 kb insertion originates from chromosome 8q24.3, segregates fully with the disease in the two families, and is absent from the general population as well as 627 neurologically normal chromosomes from in-house controls. Large insertions into chromosome Xq27.1 are known to cause a range of diseases and this is the first neuropathy phenotype caused by an interchromosomal insertion at this locus. The CMTX3 insertion represents an understudied pathogenic structural variation mechanism for inherited peripheral neuropathies. Our finding highlights the importance of considering all structural variation types when studying unsolved inherited peripheral neuropathy cases with no pathogenic coding mutations.
authors.affiliation: Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord, New South Wales, Australia.|Sydney Medical School, University of Sydney, Camperdown, New South Wales, Australia.
authors.forename: Megan H
authors.initials: MH
authors.lastname: Brewer
authors.affiliation: Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord, New South Wales, Australia.|Sydney Medical School, University of Sydney, Camperdown, New South Wales, Australia.
authors.forename: Rabia
authors.initials: R
authors.lastname: Chaudhry
authors.affiliation: Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord, New South Wales, Australia.|Discipline of Pathology, University of Sydney, Camperdown, New South Wales, Australia.
authors.forename: Jessica
authors.initials: J
authors.lastname: Qi
authors.affiliation: Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord, New South Wales, Australia.
authors.forename: Aditi
authors.initials: A
authors.lastname: Kidambi
authors.affiliation: Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord, New South Wales, Australia.
authors.forename: Alexander P
authors.initials: AP
authors.lastname: Drew
authors.affiliation: The Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.|T.Y. Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.|Paediatrics and Child Health, University of Sydney, Camperdown, New South Wales, Australia.
authors.forename: Manoj P
authors.identifier: 0000-0003-3160-6112
authors.initials: MP
authors.lastname: Menezes
authors.affiliation: Department of Neurology, Royal Children's Hospital, Parkville, Victoria, Australia.|Murdoch Childrens Research Institute, Parkville, Victoria, Australia.|Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Monique M
authors.initials: MM
authors.lastname: Ryan
authors.affiliation: Department of Neurology, Sydney Children's Hospital, Randwick, New South Wales, Australia.|School of Women's and Children's Health, UNSW Medicine, University of New South Wales, Kensington, New South Wales, Australia.
authors.forename: Michelle A
authors.identifier: 0000-0002-4472-0902
authors.initials: MA
authors.lastname: Farrar
authors.affiliation: School of Women's and Children's Health, UNSW Medicine, University of New South Wales, Kensington, New South Wales, Australia.|Department of Medical Genetics, Sydney Children's Hospital, Randwick, New South Wales, Australia.
authors.forename: David
authors.identifier: 0000-0002-3730-0870
authors.initials: D
authors.lastname: Mowat
authors.affiliation: Department of Paediatrics, John Hunter Children's Hospital, Newcastle, New South Wales, Australia.
authors.forename: Gopinath M
authors.initials: GM
authors.lastname: Subramanian
authors.affiliation: Department of Paediatrics, Royal North Shore Hospital, St Leonards, New South Wales, Australia.|Northern Clinical School, Sydney Medical School, University of Sydney, St Leonards, New South Wales, Australia.|Department of Neurogenetics, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
authors.forename: Helen K
authors.initials: HK
authors.lastname: Young
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, United States of America.|Dr. John T. Macdonald Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Stephan
authors.initials: S
authors.lastname: Zuchner
authors.affiliation: Department of Neurology, Concord Repatriation General Hospital, Concord, New South Wales, Australia.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Reddel
authors.affiliation: Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord, New South Wales, Australia.|Sydney Medical School, University of Sydney, Camperdown, New South Wales, Australia.|Molecular Medicine, Concord Repatriation General Hospital, Concord, New South Wales, Australia.
authors.forename: Garth A
authors.initials: GA
authors.lastname: Nicholson
authors.affiliation: Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord, New South Wales, Australia.|Sydney Medical School, University of Sydney, Camperdown, New South Wales, Australia.|Molecular Medicine, Concord Repatriation General Hospital, Concord, New South Wales, Australia.
authors.forename: Marina L
authors.initials: ML
authors.lastname: Kennerson
mesh_terms: D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D002874:Chromosome Mapping; D002875:Chromosomes / Q000648:ultrastructure; D002898:Chromosomes, Human, Pair 8; D041321:Chromosomes, Human, X / Q000235:genetics; D019295:Computational Biology; D004252:DNA Mutational Analysis; D059472:Exome; D005786:Gene Expression Regulation; D015894:Genome, Human; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D016254:Mutagenesis, Insertional; D009154:Mutation