Whole Genome Sequencing Identifies a 78 kb Insertion from Chromosome 8 as the Cause of Charcot-Marie-Tooth Neuropathy CMTX3

Megan H Brewer; Rabia Chaudhry; Jessica Qi; Aditi Kidambi; Alexander P Drew; Manoj P Menezes; Monique M Ryan; Michelle A Farrar; David Mowat; Gopinath M Subramanian; Helen K Young; Stephan Zuchner; Stephen W Reddel; Garth A Nicholson; Marina L Kennerson

doi:10.1371/journal.pgen.1006177

Whole Genome Sequencing Identifies a 78 kb Insertion from Chromosome 8 as the Cause of Charcot-Marie-Tooth Neuropathy CMTX3

PLoS Genet. 2016 Jul 20;12(7):e1006177. doi: 10.1371/journal.pgen.1006177. eCollection 2016 Jul.

Authors

Megan H Brewer^{1

2}, Rabia Chaudhry^{1

2}, Jessica Qi^{1

3}, Aditi Kidambi¹, Alexander P Drew¹, Manoj P Menezes^{4

5

6}, Monique M Ryan^{7

8

9}, Michelle A Farrar^{10

11}, David Mowat^{11

12}, Gopinath M Subramanian¹³, Helen K Young^{14

15

16}, Stephan Zuchner^{17

18}, Stephen W Reddel¹⁹, Garth A Nicholson^{1

2

20}, Marina L Kennerson^{1

2

20}

Affiliations

¹ Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord, New South Wales, Australia.
² Sydney Medical School, University of Sydney, Camperdown, New South Wales, Australia.
³ Discipline of Pathology, University of Sydney, Camperdown, New South Wales, Australia.
⁴ The Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
⁵ T.Y. Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
⁶ Paediatrics and Child Health, University of Sydney, Camperdown, New South Wales, Australia.
⁷ Department of Neurology, Royal Children's Hospital, Parkville, Victoria, Australia.
⁸ Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
⁹ Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.
¹⁰ Department of Neurology, Sydney Children's Hospital, Randwick, New South Wales, Australia.
¹¹ School of Women's and Children's Health, UNSW Medicine, University of New South Wales, Kensington, New South Wales, Australia.
¹² Department of Medical Genetics, Sydney Children's Hospital, Randwick, New South Wales, Australia.
¹³ Department of Paediatrics, John Hunter Children's Hospital, Newcastle, New South Wales, Australia.
¹⁴ Department of Paediatrics, Royal North Shore Hospital, St Leonards, New South Wales, Australia.
¹⁵ Northern Clinical School, Sydney Medical School, University of Sydney, St Leonards, New South Wales, Australia.
¹⁶ Department of Neurogenetics, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
¹⁷ John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
¹⁸ Dr. John T. Macdonald Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
¹⁹ Department of Neurology, Concord Repatriation General Hospital, Concord, New South Wales, Australia.
²⁰ Molecular Medicine, Concord Repatriation General Hospital, Concord, New South Wales, Australia.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Charcot-Marie-Tooth Disease / genetics*
Chromosome Mapping
Chromosomes / ultrastructure
Chromosomes, Human, Pair 8*
Chromosomes, Human, X / genetics
Computational Biology
DNA Mutational Analysis
Exome
Gene Expression Regulation
Genome, Human
Genotype
Haplotypes
Humans
Male
Mutagenesis, Insertional*
Mutation

Supplementary concepts

Charcot-Marie-Tooth disease, X-linked recessive, 3

Abstract

Publication types

MeSH terms

Supplementary concepts

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