PT - JOURNAL ARTICLE AU - Linda M. Reis AU - Mohit Maheshwari AU - Jenina Capasso AU - Huban Atilla AU - Lubica Dudakova AU - Samuel Thompson AU - Lia Zitano AU - Guillermo Lay-Son AU - R. Brian Lowry AU - Jennifer Black AU - Joseph Lee AU - Ann Shue AU - Radka Kremlikova Pourova AU - Manuela Vaneckova AU - Pavlina Skalicka AU - Jana Jedlickova AU - Marie Trkova AU - Bradley Williams AU - Gabriele Richard AU - Kristine Bachman AU - Andrea H. Seeley AU - Deborah Costakos AU - Thomas M Glaser AU - Alex V. Levin AU - Petra Liskova AU - Jeffrey C. Murray AU - Elena V. Semina TI - Axenfeld-Rieger syndrome: more than meets the eye AID - 10.1136/jmg-2022-108646 DP - 2022 Jul 26 TA - Journal of Medical Genetics PG - jmedgenet-2022-108646 4099 - http://jmg.bmj.com/content/early/2022/07/25/jmg-2022-108646.short 4100 - http://jmg.bmj.com/content/early/2022/07/25/jmg-2022-108646.full AB - Background Axenfeld-Rieger syndrome (ARS) is characterised by typical anterior segment anomalies, with or without systemic features. The discovery of causative genes identified ARS subtypes with distinct phenotypes, but our understanding is incomplete, complicated by the rarity of the condition.Methods Genetic and phenotypic characterisation of the largest reported ARS cohort through comprehensive genetic and clinical data analyses.Results 128 individuals with causative variants in PITX2 or FOXC1, including 81 new cases, were investigated. Ocular anomalies showed significant overlap but with broader variability and earlier onset of glaucoma for FOXC1-related ARS. Systemic anomalies were seen in all individuals with PITX2-related ARS and the majority of those with FOXC1-related ARS. PITX2-related ARS demonstrated typical umbilical anomalies and dental microdontia/hypodontia/oligodontia, along with a novel high rate of Meckel diverticulum. FOXC1-related ARS exhibited characteristic hearing loss and congenital heart defects as well as previously unrecognised phenotypes of dental enamel hypoplasia and/or crowding, a range of skeletal and joint anomalies, hypotonia/early delay and feeding disorders with structural oesophageal anomalies in some. Brain imaging revealed highly penetrant white matter hyperintensities, colpocephaly/ventriculomegaly and frequent arachnoid cysts. The expanded phenotype of FOXC1-related ARS identified here was found to fully overlap features of De Hauwere syndrome. The results were used to generate gene-specific management plans for the two types of ARS.Conclusion Since clinical features of ARS vary significantly based on the affected gene, it is critical that families are provided with a gene-specific diagnosis, PITX2-related ARS or FOXC1-related ARS. De Hauwere syndrome is proposed to be a FOXC1opathy.All data relevant to the study are included in the article or uploaded as supplementary information. Data availability statement: all data relevant to the study are included in the article or uploaded as supplementary information. PITX2 and FOXC1 variants identified in this study were submitted to ClinVar.