A genetic and historical perspective on the origins of keratitis fugax hereditaria

Abstract

Abstract Purpose To investigate the genetic and genealogical background of keratitis fugax hereditaria (KFH), a periodic corneal disease caused by the heterozygous pathogenic variant c.61G>C in the NLRP3 gene. KFH is characterized by recurrent unilateral autoinflammatory attacks alternating between the eyes and permanent corneal opacities. Methods Single‐nucleotide polymorphism genotyping was performed in 91 individuals from 29 families. Phased haplotypes and recombination breakpoints around the NLRP3 locus were analysed. Genealogical data were collected from 32 Finnish families with KFH, including 107 genetically confirmed patients, and extended to 2756 ancestors using interviews, population registers and historical church records. Results All families shared a common haplotype surrounding the disease variant, although centromeric and telomeric recombination breakpoints were variable. Differences in common haplotype lengths were consistent with varying degrees of relatedness. Genealogical data were complete for 11 families and partial for 17. Ancestral birthplaces clustered in southwestern Finland, and several families shared distant common ancestors from the mid‐to‐late 1600s, forming four principal lineages originating from a restricted geographic area. Conclusion The NLRP3 c.61G>C variant likely originated in southwestern Finland and appears to have been present in the population for at least 350 years. Genealogical reconstruction and haplotype analysis support a single ancestral origin, followed by lineage‐specific divergence and regional expansion. In the context of Finland's population history, these findings indicate long‐term regional enrichment of the variant and provide a historical framework for understanding its present‐day distribution.