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It is caused by an unstable cytosine\u2010thymine\u2010guanine repeat expansion at the\n                    <jats:italic>DMPK<\/jats:italic>\n                    locus, accompanied by associated genetic and epigenetic modifications. While somatic mosaicism and meiotic instability are well established, to the best of our knowledge, no study has performed a genome\u2010wide interrogation for global inherited instability. Performing whole\u2010genome optical mapping, with sequence base\u2010resolved structural variant verification, we examine global inherited genomic instability in an atypical paternally transmitted DM1 family presenting with a range of neurological manifestations, including early\u2010onset Parkinson's disease (PD). While the juvenile\u2010onset DM1 proband presented with a 10\u2010fold repeat expansion with associated hypermethylation, her partially hypermethylated asymptomatic protomutation father transmitted a 1.8\u2010fold contracted allele in the younger premutation sibling. Adult\u2010onset symptomatic DM1 and PD phenotypic paternal aunts showed significant genome\u2010wide copy number alteration, including PD\u2010associated chr19 aneuploidy loss, with additional losses on chr16, 17, and 22. In the absence of potentially pathogenic\n                    <jats:italic>de novo<\/jats:italic>\n                    or maternally inherited structural variants, the proband presented with large paternally inherited aberrations impacting gene candidates\n                    <jats:italic>CASC15<\/jats:italic>\n                    ,\n                    <jats:italic>CBFA2T3<\/jats:italic>\n                    ,\n                    <jats:italic>GPHN<\/jats:italic>\n                    ,\n                    <jats:italic>H3F3A<\/jats:italic>\n                    ,\n                    <jats:italic>SDK1<\/jats:italic>\n                    , and\n                    <jats:italic>SPAG16<\/jats:italic>\n                    , with advanced global hypomethylation. Here we suggest that inherited genomic instability may contribute to phenotypic variability, including multi\u2010neurological presentations and single\u2010generation repeat expansion or contraction. By providing a landscape of inherited large structural variants, this single\u2010family study expands knowledge of this broad and growing class of diseases. \u00a9 2026 The Author(s).\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.70084","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T08:10:37Z","timestamp":1780992637000},"page":"83-97","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Optical mapping reveals a higher level of large\u2010scale structural variants in a family with paternally transmitted myotonic dystrophy and independent Parkinson's disease"],"prefix":"10.1002","volume":"270","author":[{"given":"Md Mehedi","family":"Hasan","sequence":"first","affiliation":[{"name":"Ancestry and Health Genomics Laboratory, Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health University of Sydney  Camperdown New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenna","family":"Craddock","sequence":"additional","affiliation":[{"name":"Ancestry and Health Genomics Laboratory, Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health University of Sydney  Camperdown New South Wales Australia"},{"name":"School of Health Systems and Public Health, University of Pretoria  Pretoria South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Gong","sequence":"additional","affiliation":[{"name":"Ancestry and Health Genomics Laboratory, Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health University of Sydney  Camperdown New South Wales Australia"},{"name":"Human Phenome Institute Fudan University  Shanghai PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth J","family":"Lyons","sequence":"additional","affiliation":[{"name":"Cancer Ecosystems Program Garvan Institute of Medical Research and The Kinghorn Cancer Centre  Darlinghurst New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor","family":"Stevanovski","sequence":"additional","affiliation":[{"name":"Genomics and Inherited Disease Program The Garvan Institute of Medical Research  Darlinghurst New South Wales Australia"},{"name":"Centre for Population Genomics The Garvan Institute of Medical Research  Darlinghurst New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjog R","family":"Chintalaphani","sequence":"additional","affiliation":[{"name":"Genomics and Inherited Disease Program The Garvan Institute of Medical Research  Darlinghurst New South Wales Australia"},{"name":"Centre for Population Genomics The Garvan Institute of Medical Research  Darlinghurst New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ira W","family":"Deveson","sequence":"additional","affiliation":[{"name":"Genomics and Inherited Disease Program The Garvan Institute of Medical Research  Darlinghurst New South Wales Australia"},{"name":"Faculty of Medicine and Health University of New South Wales  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weerachai","family":"Jaratlerdsiri","sequence":"additional","affiliation":[{"name":"Ancestry and Health Genomics Laboratory, Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health University of Sydney  Camperdown New South Wales Australia"},{"name":"Computational Genomics Group, Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health University of Sydney  Camperdown New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kishore R","family":"Kumar","sequence":"additional","affiliation":[{"name":"Genomics and Inherited Disease Program The Garvan Institute of Medical Research  Darlinghurst New South Wales Australia"},{"name":"Faculty of Medicine and Health University of New South Wales  Sydney New South Wales Australia"},{"name":"ANZAC Research Institute, Neurology Department and Molecular Medicine Laboratory, Concord Repatriation General Hospital, Sydney Local Health District University of Sydney  Concord New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4524-7280","authenticated-orcid":false,"given":"Vanessa M","family":"Hayes","sequence":"additional","affiliation":[{"name":"Ancestry and Health Genomics Laboratory, Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health University of Sydney  Camperdown New South Wales 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