Abstract
Anterior segment dysgenesis (ASD) encompasses a wide spectrum of developmental abnormalities of the anterior ocular segment, including congenital cataract, iris hypoplasia, aniridia, iridocorneal synechiae, as well as Peters, Axenfeld, and Rieger anomalies. Here, we report a large five-generation Caucasian family exhibiting atypical syndromic ASD segregating with a novel truncating variant of FOXC1. The family history is consistent with highly variable autosomal dominant symptoms including isolated glaucoma, iris hypoplasia, aniridia, cataract, hypothyroidism, and congenital heart anomalies. Whole-exome sequencing revealed a novel variant [c.313_314insA; p.(Tyr105*)] in FOXC1 that disrupts the α-helical region of the DNA-binding forkhead box domain. In vitro studies using a heterologous cell system revealed aberrant cytoplasmic localization of FOXC1 harboring the Tyr105* variant, likely precluding downstream transcription function. Meta-analysis of the literature highlighted the intrafamilial variability related to FOXC1 truncating alleles. This study highlights the clinical variability in ASD and signifies the importance of combining both clinical and molecular analysis approaches to establish a complete diagnosis.
Document Type
Report
Publication Date
2-24-2022
Digital Object Identifier (DOI)
https://doi.org/10.3390/genes13030411
Funding Information
This research was funded by The National Eye Institute Intramural Funds, grant number ZIAEY000564, ZIAEY000565.
Related Content
Planned submission to ClinVar.
Repository Citation
Ahmed, Mariya R.; Sethna, Saumil; Krueger, Laura A.; Yang, Michael B.; and Hufnagel, Robert B., "Variable Anterior Segment Dysgenesis and Cardiac Anomalies Caused by a Novel Truncating Variant of FOXC1" (2022). Biology Graduate Research. 2.
https://uknowledge.uky.edu/biology_gradpub/2
Notes/Citation Information
Published in Genes, v. 13, issue 3, 411.
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).