Novel disease‐causing variants and phenotypic features of X‐linked megalocornea

Abstract

Purpose The aim of the study was to describe the phenotype and molecular genetic causes of X‐linked megalocornea (MGC1). We recruited four British, one New Zealand, one Vietnamese and four Czech families. Methods All probands and three female carriers underwent ocular examination and Sanger sequencing of the CHRDL1 gene. Two of the probands also had magnetic resonance imaging (MRI) of the brain. Results We identified nine pathogenic or likely pathogenic and one variant of uncertain significance in CHRDL1, of which eight are novel. Three probands had ocular findings that have not previously been associated with MGC1, namely pigmentary glaucoma, unilateral posterior corneal vesicles, unilateral keratoconus and unilateral Fuchs heterochromic iridocyclitis. The corneal diameters of the three heterozygous carriers were normal, but two had abnormally thin corneas, and one of these was also diagnosed with unilateral keratoconus. Brain MRI identified arachnoid cysts in both probands, one also had a neuroepithelial cyst, while the second had a midsagittal neurodevelopmental abnormality (cavum septum pellucidum et vergae). Conclusion The study expands the spectrum of pathogenic variants and the ocular and brain abnormalities that have been identified in individuals with MGC1. Reduced corneal thickness may represent a mild phenotypic feature in some heterozygous female carriers of CHRDL1 pathogenic variants.

Snail Track Lesion with Flat Keratometry in Anterior Segment Dysgenesis Caused by a Novel FOXC1 Variant

“…Although the corneal endothelium is not reported to be affected in the majority of cases with Axenfeld-Rieger syndrome, most studies lack a detailed genotype–phenotype characterization of the keratometry and endothelial cell density. To exclude other corneal conditions with phenotypic overlap (PPCD and cornea plana), or which were reported in association with ASD (FECD), we have screened the known genetic causes [ 11 , 18 , 29 ]. No rare variants or deletions were detected [ 14 , 15 , 30 , 31 ], and CTG18.1 bi-allelic repeat lengths were both in the normal range [ 11 ].…”

“…They have been reported as a feature of posterior corneal vesicles (PCVs) [ 13 ]. They show phenotypic overlap with posterior polymorphous corneal dystrophy (PPCD) caused by pathogenic variants in OVOL2 , ZEB1, and GRHL2 [ 14 , 15 , 16 , 17 ], but no genetic cause for PCVs has been identified [ 13 ], although an association with x-linked megalocornea was noted in one case [ 18 ]. Corneas that are flatter than normal are characteristic of cornea plana, which is associated with mutations in KERA [ 19 ].…”