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A 1.35 Mb DNA fragment is inserted into the DHMN1 locus on chromosome 7q34–q36.2

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Abstract

Distal hereditary motor neuropathies predominantly affect the motor neurons of the peripheral nervous system leading to chronic disability. Using whole genome sequencing (WGS) we have identified a novel structural variation (SV) within the distal hereditary motor neuropathy locus on chromosome 7q34–q36.2 (DHMN1). The SV involves the insertion of a 1.35 Mb DNA fragment into the DHMN1 disease locus. The source of the inserted sequence is 2.3 Mb distal to the disease locus at chromosome 7q36.3. The insertion involves the duplication of five genes (LOC389602, RNF32, LMBR1, NOM1, MNX1) and partial duplication of UBE3C. The genomic structure of genes within the DHMN1 locus are not disrupted by the insertion and no disease causing point mutations within the locus were identified. This suggests the novel SV is the most likely DNA mutation disrupting the DHMN1 locus. Due to the size and position of the DNA insertion, the gene(s) directly affected by the genomic re-arrangement remains elusive. Our finding represents a new genetic cause for hereditary motor neuropathies and highlights the growing importance of interrogating the non-coding genome for SV mutations in families which have been excluded for genome wide coding mutations.

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Acknowledgments

We gratefully acknowledge the participation and contribution of family members throughout this study. This study was supported by an Australian National Health and Medical Research Project Grant (APP104668) awarded to M.L.K and G.A.N.

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Authors and Affiliations

  1. Northcott Neuroscience Laboratory, ANZAC Research Institute, University of Sydney, Concord, Sydney, 2139, Australia

    Alexander P. Drew, Anthony N. Cutrupi, Megan H. Brewer, Garth A. Nicholson & Marina L. Kennerson

  2. Molecular Medicine Laboratory, Concord Hospital, Concord, Sydney, 2139, Australia

    Garth A. Nicholson & Marina L. Kennerson

  3. Sydney Medical School, University of Sydney, Sydney, Australia

    Anthony N. Cutrupi, Megan H. Brewer, Garth A. Nicholson & Marina L. Kennerson

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  1. Alexander P. Drew
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  2. Anthony N. Cutrupi
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  4. Garth A. Nicholson
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  5. Marina L. Kennerson
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Correspondence to Alexander P. Drew or Marina L. Kennerson.

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Drew, A.P., Cutrupi, A.N., Brewer, M.H. et al. A 1.35 Mb DNA fragment is inserted into the DHMN1 locus on chromosome 7q34–q36.2. Hum Genet 135, 1269–1278 (2016). https://doi.org/10.1007/s00439-016-1720-4

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