RT Journal Article SR Electronic T1 Axenfeld-Rieger syndrome: more than meets the eye JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 368 OP 379 DO 10.1136/jmg-2022-108646 VO 60 IS 4 A1 Linda M. Reis A1 Mohit Maheshwari A1 Jenina Capasso A1 Huban Atilla A1 Lubica Dudakova A1 Samuel Thompson A1 Lia Zitano A1 Guillermo Lay-Son A1 R. Brian Lowry A1 Jennifer Black A1 Joseph Lee A1 Ann Shue A1 Radka Kremlikova Pourova A1 Manuela Vaneckova A1 Pavlina Skalicka A1 Jana Jedlickova A1 Marie Trkova A1 Bradley Williams A1 Gabriele Richard A1 Kristine Bachman A1 Andrea H. Seeley A1 Deborah Costakos A1 Thomas M Glaser A1 Alex V. Levin A1 Petra Liskova A1 Jeffrey C. Murray A1 Elena V. Semina YR 2023 UL http://jmg.bmj.com/content/60/4/368.abstract 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.