Human Genetics Publications

Translational animal model for genetic predisposition to anophthalmia/microphthalmia

Document Type

Article

Publication Date

9-2026

Abstract

Anophthalmia and microphthalmia (A/M) are severe congenital malformations that are responsible for ∼11% of childhood blindness. Despite clinical advances, approximately 70-80% of human A/M cases lack a molecular diagnosis. This study aims to characterize a spontaneous, non-syndromic model of the microphthalmia, anophthalmia, and coloboma (MAC) spectrum in the laboratory opossum (Monodelphis domestica), providing a novel experimental opportunity for embryonic developmental and ocular pathology research, as well as translational research into preventions and treatments of these conditions. We conducted comprehensive ophthalmic, macroscopic, and histopathological examinations of eleven laboratory opossums with clinical A/M. Serial coronal sections of the head and of major viscera were evaluated for other developmental and systemic anomalies. Genetic influence was assessed via pedigree analysis and heritability modeling. Histopathology revealed a spectrum ranging from true anophthalmia (absence of ocular structures and optic nerve) to severe microphthalmia with retinal dysplasia and aphakia. One female exhibited a posterior choroidal and scleral coloboma, confirming the model's representation of the MAC spectrum. Systemic evaluation confirmed the non-syndromic nature of the defects. Pedigree analysis identified a predominantly X-linked recessive mode of inheritance with reduced penetrance and an estimated X-linked heritability of 0.568. Subclinical pathology, including retinal atrophy and cataracts, was identified in the fellow eyes of unilateral cases, mirroring the variable expressivity. Monodelphis domestica is a unique mammalian model that parallels the genetic and phenotypic heterogeneity of human non-syndromic A/M. This model is particularly valuable for investigating X-linked candidate genes and autosomal modifier genes in relation to the molecular mechanisms underlying mammalian ocular embryogenesis.

Comments

Not open access.

Publication Title

Experimental Eye Research

DOI

10.1016/j.exer.2026.111139

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