Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Variable Anterior Segment Dysgenesis And Cardiac Anomalies Caused By A Novel Truncating Variant Of FOXC1

Version 1 : Received: 27 January 2022 / Approved: 31 January 2022 / Online: 31 January 2022 (13:36:18 CET)

A peer-reviewed article of this Preprint also exists.

Ahmed, M.R.; Sethna, S.; Krueger, L.A.; Yang, M.B.; Hufnagel, R.B. Variable Anterior Segment Dysgenesis and Cardiac Anomalies Caused by a Novel Truncating Variant of FOXC1. Genes 2022, 13, 411. Ahmed, M.R.; Sethna, S.; Krueger, L.A.; Yang, M.B.; Hufnagel, R.B. Variable Anterior Segment Dysgenesis and Cardiac Anomalies Caused by a Novel Truncating Variant of FOXC1. Genes 2022, 13, 411.

Journal reference: Genes 2022, 13, 411
DOI: 10.3390/genes13030411

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, congenital heart anomalies, and cystic kidney disease. Whole exome sequencing revealed a novel variant [c.313_314insA; p.(Tyr105*)] in FOXC1 that disrupts the alpha-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; in vitro studies; novel variant; ophthalmic genetics; intrafamilial variability; anterior segment dysgenesis

Subject

MEDICINE & PHARMACOLOGY, Ophthalmology

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