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Here, we aimed to functionally assess the involvement of seven potentially non-canonical splicing variants on missplicing of exon 6, which represents the main hotspot region for loss-of-function <jats:italic>PAX6<\/jats:italic> variants.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>By locus-specific analysis of <jats:italic>PAX6<\/jats:italic> using Sanger and\/or targeted next-generation sequencing, we screened a Spanish cohort of 106 patients with <jats:italic>PAX6<\/jats:italic>-related diseases. Functional splicing assays were performed by in vitro minigene approaches or directly in RNA from patient-derived lymphocytes cell line, when available.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Five out seven variants, including three synonymous changes, one small exonic deletion and one non-canonical splice variant, showed anomalous splicing patterns yielding partial exon skipping and\/or elongation.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>We describe new spliceogenic mechanisms for <jats:italic>PAX6<\/jats:italic> variants mediated by creating or strengthening five different cryptic donor sites at exon 6. Our work revealed that the activation of cryptic <jats:italic>PAX6<\/jats:italic> splicing sites seems to be a recurrent and underestimated cause of aniridia. Our findings pointed out the importance of functional assessment of apparently silent <jats:italic>PAX6<\/jats:italic> variants to uncover hidden genetic alterations and to improve variant interpretation for genetic counselling in aniridia.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmedgenet-2020-106932","type":"journal-article","created":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T13:27:30Z","timestamp":1617024450000},"page":"428-437","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":9,"title":["Activation of cryptic donor splice sites by non-coding and coding <i>PAX6<\/i> variants contributes to congenital aniridia"],"prefix":"10.1136","volume":"59","author":[{"given":"Maria","family":"Tarilonte","sequence":"first","affiliation":[{"name":"Department of Genetics & Genomics, Instituto de Investigaci\u00f3n Sanitaria - Fundaci\u00f3n Jim\u00e9nez D\u00edaz University Hospital - Universidad Aut\u00f3noma de 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