Novel variants in CDH2 are associated with a new syndrome including Peters anomaly

Abstract

Peters anomaly (PA) is a congenital corneal opacity associated with corneo-lenticular attachments. PA can be isolated or part of a syndrome with most cases remaining genetically unsolved. Exome sequencing of a trio with syndromic PA and 145 additional unexplained probands with developmental ocular conditions identified a de novo splicing and three novel missense heterozygous CDH2 variants affecting the extracellular cadherin domains in four individuals with PA. Syndromic anomalies were seen in three individuals and included left-sided cardiac lesions, dysmorphic facial features, and decreasing height percentiles; brain magnetic resonance imaging identified agenesis of the corpus callosum and hypoplasia of the inferior cerebellar vermis. CDH2 encodes for N-cadherin, a transmembrane protein that mediates cell-cell adhesion in multiple tissues. Immunostaining in mouse embryonic eyes confirmed N-cadherin is present in the lens stalk at the time of separation from the future cornea and in the developing lens and corneal endothelium at later stages, supporting a possible role in PA. Previous studies in animal models have noted the importance of Cdh2/cdh2 in the development of the eye, heart, brain, and skeletal structures, also consistent with the patient features presented here. Examination of CDH2 in additional patients with PA is indicated to confirm this association.

Keywords: CDH2; N-cadherin; Peters anomaly; Peters plus syndrome; agenesis corpus callosum; left-sided cardiac lesion.

Figure 1.. Clinical images (A-O) and novel CDH2 alleles (P,Q) of individuals with syndromic and isolated Peters Anomaly.

Facial photographs of Patient 1 at 3 months of age before corneal transplant (A) and at 3 years of age (B-C) and of Patient 3 in infancy (D) and at 7 years of age (E). Optical coherence tomography of the eye showing iridocorneal adhesions (F) and retinal images showing mild optic nerve cupping but otherwise normal retinal development (G-H) from Patient 1. Brain MRI images from Patient 1 (I-K) and 3 (L-O). Sagittal noncontrast T1-weighted image from Patient 1 (I) shows complete agenesis of the corpus callosum with absence of the cingulate gyrus and radial orientation of cerebral sulci. There is minimal hypoplasia of the inferior cerebellar vermis (white arrow). Axial T2-weighted image (J) shows a parallel orientation of the lateral ventricles. Coronal T2-weighted image (K) shows lateral convexity of the frontal horns due to callosal agenesis and absence of the septum pellucidum. There is also incomplete rotation of the hippocampal formations (black arrows). Sagittal noncontrast T1-weighted image from Patient 3 (L) shows complete agenesis of the corpus callosum and hypoplasia of the inferior cerebellar vermis (white arrow). There is extradural tissue displacing the torcula suggestive of a thrombosed dural sinus malformation (asterisk). Coronal (M) and axial (N and O) T2-weighted images demonstrate nonsegmented appearance of the striatum bilaterally (black arrows) and numerous foci of subependymal gray matter heterotopia (white arrowheads). There is also incomplete rotation of the hippocampal formations (M). Pedigree of Patient 1 (specified with an arrow) with CDH2 de novo allele or wild type (WT) indicated for each family member tested (left) and sequencing traces for Patient 1 and his parents (right) (P). Schematic drawing of CDH2 protein (N-cadherin) (O) with known domains of CDH2 shown and positions of the identified human variants in Patient 1-4 indicated (red arrows). (1-25, signal peptide; 26-159, propeptide; 160-267, 268-382, 383-497, 498-603 and 604-714, EC domains I-V, correspondingly; 725-745, transmembrane domain, 746-906, cytoplasmic domain).

Figure 2.. Mouse N-cadherin localization studies.

A-C. Immunostaining in mouse embryos at the time of lens vesicle separation from overlying corneal ectoderm (E10.75-E11.0). Higher magnification images (corresponding to the boxed area in A-C) of beta-catenin and N-cadherin are shown on the right. Please note N-cadherin at the locations of first cellular contact between the cells of the lens stalk region (arrows) and no positive staining of the surface ectoderm/corneal epithelium (arrowheads); however, beta-catenin is prominently localized at both locations. D. Immunostaining in the developing mouse cornea and lens at a later developmental time point (E17.5). Higher magnification images of the boxed area (d) are shown on the right. N-cadherin is restricted to the cells of the lens and corneal endothelium (arrowheads). The localization of collagen I between the lens epithelium and corneal endothelium shows the normal separation between the two tissues and the N-cadherin protein within each cell type during development.