Alternative Genetic Diagnoses in Axenfeld–Rieger Syndrome Spectrum

Abstract

Axenfeld–Rieger 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–Rieger 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–Walker 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.

Clinical and Genetic Correlation in Neurocristopathies: Bridging a Precision Medicine Gap

“…Further data confirm the involvement of TGFβ (through a pathway that includes PITX2 and FOXC1) in the propriate formation of ocular structures in humans too, thus proving the contribution of these molecules to ocular abnormalities present in ARS [52]. FOXC1 is also active in premigratory or migrating cardiac neural crest cells as well as in tissues located near the pathways of migration, explaining in this way the nonocular multisystemic impacts of ARS [50]. Other genes that are responsible for some of the aspects of the syndrome in a small amount of individuals include CYP1B1, PRDM5, JAG1, USP9X, CDK13, HCCS, AMELX and BCOR [50,53].…”

“…The pathophysiology of this syndrome is associated with disrupted neural crest migration in the early stages of embryogenesis. Two major genes that have been proved to be responsible for this syndrome are PITX2 and FOXC1 [49,50]. Both Pitx2 and Foxc1 in mouse embryos are transcription factors that are regulated by Tgfβ, a signaling molecule that aids the neural crest cells in their migration, guiding them towards the periocular mesenchyme, and controls ocular development [51].…”

“…FOXC1 is also active in premigratory or migrating cardiac neural crest cells as well as in tissues located near the pathways of migration, explaining in this way the nonocular multisystemic impacts of ARS [50]. Other genes that are responsible for some of the aspects of the syndrome in a small amount of individuals include CYP1B1, PRDM5, JAG1, USP9X, CDK13, HCCS, AMELX and BCOR [50,53].…”