Genetic Studies on Multiple Consanguineous Families Segregating Diverse Phenotypes of Microphthalmia Identified Novel and Recurrent Mutations.

introductionAnophthalmia/microphthalmia (A/M) and anterior segment dysgenesis (ASD) are severe ocular anomalies impacting eye morphology, occurring in 30 per 100,000 live births. Genetic research has identified over 30 genes linked to A/M anomalies, with their products mainly involved in eye organogenesis. AIMS AND

objectivesThis study examined two consanguineous A/M families to identify disease-associated pathogenic mutations and predict their functional impact. METHODOLOGY: Patients were clinically examined using A-scan and ophthalmic ultrasonography. Whole exome sequencing (WES) identified candidate pathogenic variants validated through Sanger sequencing. Computational analyses assessed the impact of these mutations on protein structure and function.

resultsThe clinical diagnosis of family A revealed microphthalmia with ASD, while family B presented with an A/M phenotype. Exome analysis of family A identified a novel missense variant, NM_012293:c.A3742G [p.(Arg1248Gly)], in the peroxidasin (PXDN) gene (ClinVar ID: VCV001333267.1). At the cellular level, PXDN is involved in establishing sulfilimine bonds in collagen IV, a component of the basement membrane, suggesting that ocular defects may result from impaired integrity of the basement membrane in the developing eye. In contrast, Family B exhibited a nonsense variant NM _012186:c.720C>A (p.- Cys240*) in the FOXE3 gene. This variant has been previously reported in other South Asian populations, suggesting a founder effect in subcontinent populations. Structural modeling and simulation analysis of mutant proteins revealed altered properties, thus corroborating the pathogenicity of the identified mutation.

conclusionOur findings may contribute to the elucidation of genotype-phenotype correlations, potentially facilitating the molecular diagnosis of microphthalmia and ASD.