{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T04:12:20Z","timestamp":1772683940223,"version":"3.50.1"},"posted":{"date-parts":[[2025,6,6]]},"group-title":"Genetic and Genomic Medicine","reference-count":24,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T00:00:00Z","timestamp":1749168000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,6,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Axenfeld\u2013Rieger Syndrome (ARS) is an autosomal dominant condition with both ocular and non-ocular manifestations. ARS is primarily caused by coding variants at the\n                  <jats:italic>PITX2<\/jats:italic>\n                  or\n                  <jats:italic>FOXC1<\/jats:italic>\n                  loci, yet many cases still remain undiagnosed. Here we used whole-genome sequencing to identify two non-coding structural variants associated with a typical presentation of\n                  <jats:italic>PITX2<\/jats:italic>\n                  -associated ARS: one with a 450 kb deletion removing a series of conserved enhancer elements distal to\n                  <jats:italic>PITX2<\/jats:italic>\n                  , and the second with a 12.5 Mb inversion displacing the\n                  <jats:italic>PITX2<\/jats:italic>\n                  gene from these same enhancer elements. Neither variant disrupted the\n                  <jats:italic>PITX2<\/jats:italic>\n                  gene itself, and therefore both were expected to reduce\n                  <jats:italic>PITX2<\/jats:italic>\n                  expression by disrupting its proximity or access to enhancer elements. Enhancer-disrupting intergenic inversions therefore represent a unique genetic mechanism for the development of ARS, which should be carefully considered in the context of ARS and other conditions without a conclusive genetic diagnosis.\n                <\/jats:p>","DOI":"10.1101\/2025.06.05.25327661","type":"posted-content","created":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T21:10:32Z","timestamp":1749244232000},"source":"Crossref","is-referenced-by-count":2,"title":["Axenfeld-Rieger syndrome associated with a megabase-scale inversion separating\n                  <i>PITX2<\/i>\n                  from a conserved enhancer locus"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5160-3299","authenticated-orcid":false,"given":"Lucas A.","family":"Mitchell","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joshua","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emmanuelle","family":"Souzeau","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lachlan S. W.","family":"Knight","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giorgina","family":"Maxwell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"Dubowsky","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ridia","family":"Lim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward","family":"Formaini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew","family":"Welland","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cas","family":"Simons","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel G.","family":"MacArthur","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janey L.","family":"Wiggs","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jamie E.","family":"Craig","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2840-4851","authenticated-orcid":false,"given":"Owen 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