BACKGROUND:PIKFYVE, a novel pathogenic gene causing congenital cataract, its association with sporadic cataracts has not been systematically investigated. This study aimed to explore PIKFYVE mutation profiles in major sporadic cataract subtypes. METHODS:We enrolled 322 sporadic cataract cases including 240 age-related cataract cases, 63 diabetes mellitus cataract cases and 19 high myopic cataract cases. One hundred seventy non -cataract individuals were enrolled as controls. PIKFYVE variants were initially screened using FastTarget region sequencing and validated by Sanger sequencing. Pathogenic impacts of variants were assessed using SIFT, PolyPhen-2, MutationTaster, ClinPred, ACMG and gnomAD databases, as well as Protein Three-Dimensional Structure Prediction and protein-protein interaction analysis. RESULTS:Eight PIKFYVE variants were identified in these cataract cases, including two novel variants (c.881T > A and c.4027C > T), and six known variants (c.1051-4G > T; c.1654A > G; c.2795C > G; c.5335G > T; c.5399A > C; and c.5594C > T). Among these variants, three variants (c.2795C > G; c.4027C > T; and c.5335G > T) were predicted to be in silico predicted deleterious on PIKFYVE protein function and alter normal protein conformation. CONCLUSIONS:We identified two novel variants and three in silico predicted deleterious variants on PIKFYVE gene in sporadic cataract patients. These findings expand the PIKFYVE mutation spectrum and indicate that PIKFYVE variants may potentially contribute to sporadic cataract pathogenesis.
Posterior polymorphous corneal dystrophy type 3 (PPCD3) is an autosomal dominant endothelial dystrophy caused by variations in the ZEB1 gene. We report a pediatric case presenting with progressive visual impairment associated with simultaneous features of corneal ectasia and endothelial dystrophy. A 9-year-old boy presented with progressive diminution of vision and high myopia. Slit-lamp examination revealed prominent corneal nerves, and central corneal steepening, along with diffuse endothelial guttae and a beaten-metal appearance of the endothelium. Multimodal imaging including Scheimpflug tomography that demonstrated marked bilateral corneal steepening with tomographic features suggestive of corneal ectasia (Kmax 59.0 D in the right eye and 61.6 D in the left eye). Interestingly, central corneal thickness was increased (636 µm in the right eye and 659 µm in the left eye), feature atypical of keratoconus. Specular microscopy demonstrated reduced endothelial cell density. Whole-exome sequencing of the proband identified a novel heterozygous splice-site variant in ZEB1 (chr10:g.31510671A > T; c.485-2A > T), affecting the canonical 3' splice acceptor site. Targeted next-generation sequencing of parental blood samples confirmed the variant in the father (heterozygous) and its absence in mother, consistent with paternal inheritance. This case provides additional evidence supporting the recognized association between ZEB1-related PPCD3 and suspected corneal ectasia, while describing a novel splice-site ZEB1 variant.
