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. 2023 Oct 17;14(10):1948.
doi: 10.3390/genes14101948.

Alternative Genetic Diagnoses in Axenfeld-Rieger Syndrome Spectrum

Linda M Reis  1   2 , David J Amor  3 , Raad A Haddad  4 , Catherine B Nowak  5 , Kim M Keppler-Noreuil  6 , Smith Ann Chisholm  1 , Elena V Semina  1   2
Affiliations

Alternative Genetic Diagnoses in Axenfeld-Rieger Syndrome Spectrum

Linda M Reis et al. Genes (Basel). .

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.

Keywords: AMELX; Axenfeld–Rieger anomaly; Axenfeld–Rieger syndrome; BCOR; CDK13; HCCS; JAG1; USP9X.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Selected ocular images demonstrating anterior segment phenotypes. (A) Right eye of Individual 2 showing corneal ectasia with large bulbous anterior extension. (B) Eye of Individual 5 showing posterior embryotoxon and mild iris hypoplasia (C,D) Bilateral eye images of Individual 6 showing severe corectopia, posterior embryotoxon and iris hypoplasia.
See this image and copyright information in PMC

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