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In 19 out of 22 families, the causative genomic changes have an interpretable deleterious impact on the\n<jats:italic>PAX6<\/jats:italic>\nlocus. Of these 19 families, 1 has a novel heterozygous\n<jats:italic>PAX6<\/jats:italic>\nframeshift variant missed on previous screens, 4 have single nucleotide variants (SNVs) (one novel) affecting essential splice sites of\n<jats:italic>PAX6<\/jats:italic>\n5\u2032 non-coding exons and 2 have deep intronic SNV (one novel) resulting in gain of a donor splice site. In 12 out of 19, the causative variants are large-scale structural variants; 5 have partial or whole gene deletions of\n<jats:italic>PAX6<\/jats:italic>\n, 3 have deletions encompassing critical\n<jats:italic>PAX6 cis<\/jats:italic>\n-regulatory elements, 2 have balanced inversions with disruptive breakpoints within the\n<jats:italic>PAX6<\/jats:italic>\nlocus and 2 have complex rearrangements disrupting\n<jats:italic>PAX6<\/jats:italic>\n. The remaining 3 of 22 families have deletions encompassing\n<jats:italic>FOXC1<\/jats:italic>\n(a known cause of atypical aniridia). Seven of the causative variants occurred\n<jats:italic>de novo<\/jats:italic>\nand one cosegregated with familial aniridia. We were unable to establish inheritance status in the remaining probands. No plausibly causative SNVs were identified in\n<jats:italic>PAX6 cis<\/jats:italic>\n-regulatory elements.\n<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Conclusion<\/jats:title>\n<jats:p>Whole genome sequencing proves to be an effective diagnostic test in most individuals with previously unexplained aniridia.<\/jats:p>\n<\/jats:sec>","DOI":"10.1136\/jmg-2023-109181","type":"journal-article","created":{"date-parts":[[2023,12,1]],"date-time":"2023-12-01T03:46:01Z","timestamp":1701402361000},"page":"250-261","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":8,"title":["Short-read whole genome sequencing identifies causative variants in most individuals with previously unexplained aniridia"],"prefix":"10.1136","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7082-1523","authenticated-orcid":false,"given":"Hildegard Nikki","family":"Hall","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Parry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihail","family":"Halachev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen A","family":"Williamson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Donnelly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose","family":"Campos Parada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shipra","family":"Bhatia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Joseph","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Holden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trine E","family":"Prescott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Bitoun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edwin P","family":"Kirk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth","family":"Newbury-Ecob","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Lachlan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Bernar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"van Heyningen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R","family":"FitzPatrick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison","family":"Meynert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2023,11,30]]},"reference":[{"key":"2024091209100810000_61.3.250.1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"2024091209100810000_61.3.250.2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2017.210"},{"key":"2024091209100810000_61.3.250.3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2035790"},{"key":"2024091209100810000_61.3.250.4","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-022-01073-3"},{"key":"2024091209100810000_61.3.250.5","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-018-1934-8"},{"key":"2024091209100810000_61.3.250.6","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00295-1"},{"key":"2024091209100810000_61.3.250.7","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1005193","article-title":"Functional assessment of disease-associated regulatory variants in vivo using a versatile dual colour transgenesis strategy in zebrafish","volume":"11","author":"Bhatia","year":"2015","journal-title":"PLoS Genet"},{"key":"2024091209100810000_61.3.250.8","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1890410"},{"key":"2024091209100810000_61.3.250.9","unstructured":"Li H . 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