PIKFYVE – Fleck Corneal Dystrophy

Fleck corneal dystrophy (FCD) is a rare Autosomal dominant stromal dystrophy characterized by scattered white flecks throughout all layers of the cornea, leading to visual impairment (HP:0000505) and metamorphopsia (HP:0012508). Heterozygous loss-of-function variants in PIKFYVE have been identified in both sporadic and familial cases of FCD. A 63-year-old Japanese woman presented with decreased vision and metamorphopsia; sequencing revealed a novel heterozygous c.4166_4169delAAGT (p.Glu1389AspfsTer16) variant in exon 24 of PIKFYVE, predicted to truncate the kinase and FYVE domains (PMID:23288988).

A second report described a 19-year-old male and his asymptomatic father, both harboring a heterozygous deletion of the entire PIKFYVE coding region detected by NGS and confirmed by CMA and qPCR; the variant segregated with FCD in this family (PMID:38956867). These two unrelated probands and one additional affected relative provide limited case-level evidence. Experimental data support haploinsufficiency as the mechanism: complete gene deletion causes corneal keratocyte dysfunction, although heterozygous Pikfyve(+/–) mice are phenotypically normal (PMID:21349843), and no cornea-specific in vivo model recapitulates FCD.

Based on two probands, one segregation, and minimal functional modeling, the gene-disease association is classified as Limited. Genetic evidence is Limited (2 probands [PMID:23288988], [PMID:38956867]; 1 affected relative [PMID:38956867]). Functional evidence is Limited (haploinsufficiency suggested by deletion case [PMID:38956867]; heterozygous mice normal [PMID:21349843]).

Key Take-home: Heterozygous truncating and whole-gene deletion variants in PIKFYVE underlie Autosomal dominant fleck corneal dystrophy, warranting incorporation of PIKFYVE testing in clinical FCD panels.

References

• Molecular Vision • 2012 • A novel mutation (p.Glu1389AspfsX16) of the phosphoinositide kinase, FYVE finger containing gene found in a Japanese patient with fleck corneal dystrophy. PMID:23288988
• Ophthalmic Genetics • 2024 • Familial fleck corneal dystrophy caused by complete deletion of the PIKFYVE gene. PMID:38956867
• The Journal of Biological Chemistry • 2011 • The phosphoinositide kinase PIKfyve is vital in early embryonic development: preimplantation lethality of PIKfyve-/- embryos but normality of PIKfyve+/- mice. PMID:21349843

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