Variable Anterior Segment Dysgenesis and Cardiac Anomalies Caused by a Novel Truncating Variant of FOXC1

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.

Keywords: FOXC1; anterior segment dysgenesis; in vitro studies; intrafamilial variability; novel variant; ophthalmic genetics.

Figure 1

(a) Numbered individuals received a dilated eye examination. The predominant phenotype was congenital glaucoma, while other ocular and nonocular abnormalities exhibited variable expression; (b) slit lamp analysis revealed multiple eye problems. The proband (IV-1) is a 38-year-old female with congenital glaucoma, bilateral iris hypoplasia, and hypothyroidism. Family history is consistent with a highly variable autosomal dominant condition that includes isolated glaucoma (III-01), iris hypoplasia (IV-01), aniridia (V-02), cataract, hypothyroidism, and congenital heart anomalies; (c) representative Sanger sequencing chromatograms of FOXC1 exon from a normal (V-1) and an affected (V-2) individuals of family LNG5, showing the c.313_314insA allele. All individuals included within the LNG5 pedigree were tested with Sanger sequencing to confirm segregation and full phenotypic penetrance; (d) schematic representation of FOXC1 gene and protein structure. Two nuclear localization signals (NLS1 and NLS2) are present at both ends of the DNA-binding forkhead box domain (FH). FOXC1 c.313_314insA [p.(Tyr105*)] disrupts the α-helical region of the FH domain and removes NLS2 along with the carboxy tail. H—Helix. B—β-sheets. W—Winged helix.

Figure 2

Representative images of COS-7 cells transiently transfected with tomato-tagged wild-type (WT) or FOXC1 constructs. As compared to WT-FOXC1, which is primarily localized in the nucleus, the truncated FOXC1 was also found in the cytoplasm. Scale bar—10 µm.

Figure 3

Prevalence of the commonly occurring clinical features among 56 individuals from 12 families affected with truncating variants of FOXC1 from Table 1 (n = 56 individuals).