Novel mutations of PIKFYVE identified in 322 sporadic cataract patients

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.

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.

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.

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.