{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T09:01:17Z","timestamp":1788080477582,"version":"build-2784847793"},"posted":{"date-parts":[[2023,8,21]]},"group-title":"Neurology","reference-count":43,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,8,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    <jats:italic>PRKN<\/jats:italic>\n                    mutations are the most common cause of young onset and autosomal recessive Parkinson\u2019s disease (PD).\n                    <jats:italic>PRKN<\/jats:italic>\n                    is located in FRA6E which is one of the common fragile sites in the human genome, making this region prone to structural variants. However, complex structural variants such as inversions of\n                    <jats:italic>PRKN<\/jats:italic>\n                    are seldom reported, suggesting that there are potentially unrevealed complex pathogenic\n                    <jats:italic>PRKN<\/jats:italic>\n                    structural variants.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>\n                    To identify complex structural variants in\n                    <jats:italic>PRKN<\/jats:italic>\n                    using long-read sequencing.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    We investigated the genetic cause of monozygotic twins presenting with a young onset dystonia-parkinsonism using targeted sequencing, whole exome sequencing, multiple ligation probe amplification, and long-read. We assessed the presence and frequency of complex inversions overlapping\n                    <jats:italic>PRKN<\/jats:italic>\n                    using whole-genome sequencing data of AMP-PD and UK-Biobank datasets.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Multiple ligation probe amplification identified a heterozygous exon 3 deletion in\n                    <jats:italic>PRKN<\/jats:italic>\n                    and long-read sequencing identified a large novel inversion spanning over 7Mb, including a large part of the coding DNA sequence of\n                    <jats:italic>PRKN<\/jats:italic>\n                    . We could diagnose the affected subjects as compound heterozygous carriers of\n                    <jats:italic>PRKN<\/jats:italic>\n                    . We analyzed whole genome sequencing data of 43,538 participants of the UK-Biobank and 4,941 participants of the AMP-PD datasets. Nine inversions in the UK-Biobank and two in AMP PD were identified and were considered potentially damaging and likely to affect\n                    <jats:italic>PRKN<\/jats:italic>\n                    isoforms.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>\n                    This is the first report describing a large 7Mb inversion involving breakpoints outside of\n                    <jats:italic>PRKN<\/jats:italic>\n                    . This study highlights the importance of using long-read whole genome sequencing for structural variant analysis in unresolved young-onset PD cases.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2023.08.14.23293948","type":"posted-content","created":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T18:30:32Z","timestamp":1692642632000},"source":"Crossref","is-referenced-by-count":3,"title":["Long-read sequencing resolves a complex structural variant in\n                  <i>PRKN<\/i>\n                  Parkinson\u2019s disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9177-9587","authenticated-orcid":false,"given":"Kensuke","family":"Daida","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7412-3631","authenticated-orcid":false,"given":"Manabu","family":"Funayama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberley J","family":"Billingsley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laksh","family":"Malik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail","family":"Miano-Burkhardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hampton L.","family":"Leonard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7978-1051","authenticated-orcid":false,"given":"Mary B.","family":"Makarious","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirotaka","family":"Iwaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4691-4524","authenticated-orcid":false,"given":"Jinhui","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6985-0658","authenticated-orcid":false,"given":"J. 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