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Recessive and dominant variants cause human ocular disease but the full range of phenotypes and mechanisms of action for the two classes of variants are unknown. We identified FOXE3 variants in individuals with congenital eye malformations and carried out in vitro functional analysis on selected alleles. Sixteen new recessive and dominant families, including six novel variants, were identified. Analysis of new and previously reported genetic and clinical data demonstrated a broad phenotypic range with an overlap between recessive and dominant disease. Most families with recessive alleles, composed of truncating and forkhead-domain missense variants, had severe corneal opacity (90%; sclerocornea in 47%), aphakia (83%) and microphthalmia (80%), but some had milder features including isolated cataract. The phenotype was most variable for recessive missense variants, suggesting that the functional consequences may be highly dependent on the type of amino acid substitution and its position. When assessed, aniridia or iris hypoplasia were noted in 89% and optic nerve anomalies in 60% of recessive cases, indicating that these defects are also common and may be underrecognized. In dominant pedigrees, caused by extension variants, normal eye size (96%), cataracts (99%) and variable anterior segment anomalies were seen in most, but some individuals had microphthalmia, aphakia or sclerocornea, more typical of recessive disease. Functional studies identified variable effects on the protein stability, DNA binding, nuclear localization and transcriptional activity for recessive FOXE3 variants, whereas dominant alleles showed severe impairment in all areas and dominant-negative characteristics.<\/jats:p>","DOI":"10.1093\/hmg\/ddab142","type":"journal-article","created":{"date-parts":[[2021,5,21]],"date-time":"2021-05-21T11:10:16Z","timestamp":1621595416000},"page":"1591-1606","source":"Crossref","is-referenced-by-count":23,"title":["Comprehensive phenotypic and functional analysis of dominant and recessive<i>FOXE3<\/i>alleles in ocular developmental disorders"],"prefix":"10.1093","volume":"30","author":[{"given":"Linda M","family":"Reis","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Research Institute at the Medical College of Wisconsin and Children\u2019s Hospital of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena A","family":"Sorokina","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Research Institute at the Medical College of Wisconsin and Children\u2019s Hospital of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lubica","family":"Dudakova","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, 121 08 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Moravikova","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, 121 08 Prague, Czech 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E","family":"Seese","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Research Institute at the Medical College of Wisconsin and Children\u2019s Hospital of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Thompson","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Research Institute at the Medical College of Wisconsin and Children\u2019s Hospital of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanya","family":"Bardakjian","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Albert Einstein Medical Center, Philadelphia, PA 19141, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenina","family":"Capasso","sequence":"additional","affiliation":[{"name":"Pediatric Ophthalmology and Ocular Genetics, Flaum Eye Institute, Pediatric Genetics, Golisano Children\u2019s Hospital, University of Rochester, Rochester, NY 14534 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Allen","sequence":"additional","affiliation":[{"name":"Fullerton Genetics Center, Mission Hospitals, HCA, Asheville, NC 28803 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Glaser","sequence":"additional","affiliation":[{"name":"Cell Biology and Human Anatomy Department, UC-Davis School of Medicine, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex V","family":"Levin","sequence":"additional","affiliation":[{"name":"Pediatric Ophthalmology and Ocular Genetics, Flaum Eye Institute, Pediatric Genetics, Golisano Children\u2019s Hospital, University of Rochester, Rochester, NY 14534 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adele","family":"Schneider","sequence":"additional","affiliation":[{"name":"Department of 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V","family":"Semina","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Research Institute at the Medical College of Wisconsin and Children\u2019s Hospital of Wisconsin, Milwaukee, WI 53226, USA"},{"name":"Departments of Ophthalmology and Visual Sciences and Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,5,27]]},"reference":[{"key":"2021081712011360000_ref1","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1093\/hmg\/10.3.231","article-title":"Mutations in the human forkhead transcription factor FOXE3 associated with anterior segment ocular dysgenesis and cataracts","volume":"10","author":"Semina","year":"2001","journal-title":"Hum. 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