Novel heterozygous variants in PXDN cause different anterior segment dysgenesis phenotypes in monozygotic twins.

Background: Since bi-allelic variants in the PXDN gene were first discovered in 2011 to be associated with anterior segment dysgenesis, a spectrum of ophthalmologic and systemic clinical manifestations has been described. This manuscript reports two distinct clinical phenotypes in monozygotic twin sisters, including the previously unreported ocular manifestation of bilateral primary aphakia, associated with novel compound heterozygous variants in the PXDN gene.
Materials and Methods: We used genome sequencing to study a non-consanguineous family with monozygotic twin sister probands: one presenting with bilateral microphthalmia, primary aphakia, total corneal opacification, congenital glaucoma, and complex systemic comorbidities; the other with anterior persistent fetal vasculature in the right eye, and Peters anomaly type 2 with cataract and iris coloboma in the left eye but no systemic issues. These findings were compared to published reports of PXDN -related ocular diseases upon comprehensive review of prior literature.
Results: In both affected sisters, genome sequencing identified two novel heterozygous variants in trans in the PXDN gene: c.1569_1570insT, predicting p.(Thr524TyrfsTer53), and c.3206 C > A, predicting p.(Ala1069Asp), respectively. No other potentially diagnostic variants were identified in any other genes.
Conclusions: This report on two novel compound heterozygous variants in the PXDN gene associated with previously unreported clinical manifestations further expands the genotypic and phenotypic spectrum associated with this gene. Our finding of distinctive clinical phenotypes associated with identical compound heterozygous PXDN variants in monozygotic twins emphasizes the significant clinical variability that can occur, suggesting a potential role for stochastic developmental and/or epigenetic factors in the ultimate pathophysiologic pathway.