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In addition to single nucleotide variants, structural variants contribute substantially to the mutational profile of\n                      <jats:italic>PRKN<\/jats:italic>\n                      . A significant portion of patients with EOPD remains genetically unsolved.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>\n                      By using short\u2010read whole genome sequencing (sr\u2010WGS), we aimed to uncover complex genetic alterations at the\n                      <jats:italic>PRKN<\/jats:italic>\n                      locus in EOPD cases which tested negative for mutations in Mendelian PD genes with clinical exome sequencing (CES) and multiplex ligation\u2010dependent probe amplification (MLPA).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We evaluated 498 unrelated EOPD patients, who tested negative using gold\u2010standard diagnostic methods, using sr\u2010WGS. In selected cases, long\u2010read whole genome sequencing (lr\u2010WGS) with Oxford Nanopore technology was employed for an in\u2010depth analysis and validation. The Parkinson's Progression Markers Initiative (PPMI) dataset was interrogated to assess the prevalence of any newly identified elusive pathogenic genetic configurations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      sr\u2010WGS revealed elusive compound heterozygous structural variations, consisting of partially overlapping deletions and duplications within the\n                      <jats:italic>PRKN<\/jats:italic>\n                      gene in three unrelated EOPD cases (two familial, one sporadic). In familial cases, biallelic\n                      <jats:italic>PRKN<\/jats:italic>\n                      structural variants co\u2010segregated with the disease. The exact structure of each variant was resolved using lr\u2010WGS. Similar variants were absent in the large PPMI database, suggesting that they are a rare occurrence.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      In this article we describe a rare configuration of compound heterozygous structural variations involving partially overlapping chromosomal regions at the\n                      <jats:italic>PRKN<\/jats:italic>\n                      locus, which are difficult to detect through standard diagnostic genetic technologies. This study highlights the importance of integrating WGS into clinical practice. \u00a9 2025 The Author(s).\n                      <jats:italic>Movement Disorders<\/jats:italic>\n                      published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/mds.70027","type":"journal-article","created":{"date-parts":[[2025,8,30]],"date-time":"2025-08-30T12:05:51Z","timestamp":1756555551000},"page":"2722-2731","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Compound Heterozygous Structural Variants in Cases with Unsolved\n                    <scp>\n                      <i>PRKN<\/i>\n                    <\/scp>\n                    \u2010Associated Parkinson's Disease"],"prefix":"10.1002","volume":"40","author":[{"given":"Agata","family":"Fant","sequence":"first","affiliation":[{"name":"Non\u2010Coding RNAs and RNA\u2010Based Therapeutics Italian Institute of Technology (IIT), CMP3VdA  Aosta Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9270-4977","authenticated-orcid":false,"given":"Sara","family":"Trova","sequence":"additional","affiliation":[{"name":"Non\u2010Coding RNAs and RNA\u2010Based Therapeutics Italian Institute of Technology (IIT), CMP3VdA  Aosta Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4720-9234","authenticated-orcid":false,"given":"Edoardo","family":"Monfrini","sequence":"additional","affiliation":[{"name":"Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation University of Milan  Milan Italy"},{"name":"Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Neurology 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