{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T12:44:18Z","timestamp":1791895458389,"version":"4.3.4"},"reference-count":38,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,10,17]],"date-time":"2023-10-17T00:00:00Z","timestamp":1697500800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R01EY015518"],"award-info":[{"award-number":["R01EY015518"]}]},{"name":"NIH","award":["R01EY025718"],"award-info":[{"award-number":["R01EY025718"]}]},{"name":"Children\u2019s Research Institute Foundation at Children\u2019s Wisconsin","award":["R01EY015518"],"award-info":[{"award-number":["R01EY015518"]}]},{"name":"Children\u2019s Research Institute Foundation at Children\u2019s Wisconsin","award":["R01EY025718"],"award-info":[{"award-number":["R01EY025718"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Axenfeld\u2013Rieger anomaly (ARA) is a specific ocular disorder that is frequently associated with other systemic abnormalities. PITX2 and FOXC1 variants explain the majority of individuals with Axenfeld\u2013Rieger syndrome (ARS) but leave ~30% unsolved. Here, we present pathogenic\/likely pathogenic variants in nine families with ARA\/ARS or similar phenotypes affecting five different genes\/regions. USP9X and JAG1 explained three families each. USP9X was recently linked with syndromic cognitive impairment that includes hearing loss, dental defects, ventriculomegaly, Dandy\u2013Walker malformation, skeletal anomalies (hip dysplasia), and other features showing a significant overlap with FOXC1-ARS. Anterior segment anomalies are not currently associated with USP9X, yet our cases demonstrate ARA, congenital glaucoma, corneal neovascularization, and cataracts. The identification of JAG1 variants, linked with Alagille syndrome, in three separate families with a clinical diagnosis of ARA\/ARS highlights the overlapping features and high variability of these two phenotypes. Finally, intragenic variants in CDK13, BCOR, and an X chromosome deletion encompassing HCCS and AMELX (linked with ocular and dental anomalies, correspondingly) were identified in three additional cases with ARS. Accurate diagnosis has important implications for clinical management. We suggest that broad testing such as exome sequencing be applied as a second-tier test for individuals with ARS with normal results for PITX2\/FOXC1 sequencing and copy number analysis, with attention to the described genes\/regions.<\/jats:p>","DOI":"10.3390\/genes14101948","type":"journal-article","created":{"date-parts":[[2023,10,17]],"date-time":"2023-10-17T08:08:33Z","timestamp":1697530113000},"page":"1948","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Alternative Genetic Diagnoses in Axenfeld\u2013Rieger Syndrome Spectrum"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5098-6336","authenticated-orcid":false,"given":"Linda M.","family":"Reis","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin, Milwaukee, WI 53226, USA"},{"name":"Department of Pediatrics and Children\u2019s Research Institute, Medical College of Wisconsin and Children\u2019s Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7191-8511","authenticated-orcid":false,"given":"David J.","family":"Amor","sequence":"additional","affiliation":[{"name":"Murdoch Children\u2019s Research Institute, Department of Paediatrics, University of Melbourne, Parkville, VIC 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raad A.","family":"Haddad","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes, and Metabolic Diseases, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine B.","family":"Nowak","sequence":"additional","affiliation":[{"name":"Division of Genetics and Metabolism, MassGeneral Hospital for Children, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8250-164X","authenticated-orcid":false,"given":"Kim M.","family":"Keppler-Noreuil","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Smith Ann","family":"Chisholm","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0531-3586","authenticated-orcid":false,"given":"Elena V.","family":"Semina","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin, Milwaukee, WI 53226, USA"},{"name":"Department of Pediatrics and Children\u2019s Research Institute, Medical College of Wisconsin and Children\u2019s Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,17]]},"reference":[{"key":"ref_1","first-page":"736","article-title":"Axenfeld-Rieger syndrome: A theory of mechanism and distinctions from the iridocorneal endothelial syndrome","volume":"81","author":"Shields","year":"1983","journal-title":"Trans. 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