title: A 1.35 Mb DNA fragment is inserted into the DHMN1 locus on chromosome 7q34-q36.2.
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.
authors.affiliation: Northcott Neuroscience Laboratory, ANZAC Research Institute, University of Sydney, Concord, Sydney, 2139, Australia. adre8193@uni.sydney.edu.au.
authors.forename: Alexander P
authors.initials: AP
authors.lastname: Drew
authors.affiliation: Northcott Neuroscience Laboratory, ANZAC Research Institute, University of Sydney, Concord, Sydney, 2139, Australia.|Sydney Medical School, University of Sydney, Sydney, Australia.
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Cutrupi
authors.affiliation: Northcott Neuroscience Laboratory, ANZAC Research Institute, University of Sydney, Concord, Sydney, 2139, Australia.|Sydney Medical School, University of Sydney, Sydney, Australia.
authors.forename: Megan H
authors.initials: MH
authors.lastname: Brewer
authors.affiliation: Northcott Neuroscience Laboratory, ANZAC Research Institute, University of Sydney, Concord, Sydney, 2139, Australia.|Molecular Medicine Laboratory, Concord Hospital, Concord, Sydney, 2139, Australia.|Sydney Medical School, University of Sydney, Sydney, Australia.
authors.forename: Garth A
authors.initials: GA
authors.lastname: Nicholson
authors.affiliation: Northcott Neuroscience Laboratory, ANZAC Research Institute, University of Sydney, Concord, Sydney, 2139, Australia. marina.kennerson@sydney.edu.au.|Molecular Medicine Laboratory, Concord Hospital, Concord, Sydney, 2139, Australia. marina.kennerson@sydney.edu.au.|Sydney Medical School, University of Sydney, Sydney, Australia. marina.kennerson@sydney.edu.au.
authors.forename: Marina L
authors.initials: ML
authors.lastname: Kennerson
mesh_terms: D002874:Chromosome Mapping; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D005260:Female; D020440:Gene Duplication / Q000235:genetics; D015894:Genome, Human; D056914:Genomic Structural Variation / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000473:pathology; D016254:Mutagenesis, Insertional / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D017933:Peripheral Nervous System / Q000378:metabolism / Q000473:pathology