Familial fleck corneal dystrophy caused by complete deletion of the PIKFYVE gene

Fleck corneal dystrophy (FCD) is a rare autosomal dominant disease that affects exclusively the corneal stroma. The disease is caused by heterozygous variants in PIKFYVE, a gene encoding a lipid kinase involved in multiple cellular pathways, primarily participating in membrane dynamics and signaling. This report describes a familial case of FCD caused by a complete deletion of the PIKFYVE gene. A clinical ophthalmic examination was performed on the proband and family members. Genetic testing included next-generation sequencing (multigene panel), and chromosomal microarray analysis. A quantitative PCR assay was designed in order to segregate the deletion. A 19-year-old male, with no family or personal history of ocular disease, presented for evaluation due to an acute illness consisting of burning, foreign body sensation, and red eye. Slit lamp biomicroscopy revealed bilateral small pterygia and scattered bilateral white opacities in the corneal stroma, a very similar corneal phenotype was found in the 47-year-old father, who was asymptomatic. NGS detected a heterozygous deletion of the entire PIKFYVE coding sequence. CMA in DNA from the propositus indicated a 543 kb deletion in 2q33.3q34 spanning the entire PIKFYVE gene. The deletion was confirmed in the father. We add to the molecular spectrum of FCD by describing a familial case of a whole PIKFYVE gene deletion in affected subjects. Our findings support that normal expression of PIKFYVE is necessary for corneal keratocytes homeostasis and normal corneal appearance. We conclude that PIKFYVE haploinsufficiency is the molecular mechanism underlying this familial case of FCD.