Hereditary Congenital Cataract With Spastic Paraplegia Associated With a Missense PAX6 Variant (p.Arg26Trp)

To date, several genetic factors have been reported in cases presenting both congenital cataract (CC) and spastic paraplegia (SPG), but the overall genetic landscape of this condition remains insufficiently understood. Here, we describe the clinical, genetic, and functional findings in a single Japanese family presenting with hereditary CC and SPG. Affected individuals exhibited severe CC and mild SPG symptoms. Whole exome sequencing combined with stringent filtering revealed no pathogenic variants in the three known genes. Instead, we identified a heterozygous missense variant in PAX6 (NM_001258465, c.76C>T: p.Arg26Trp), a gene well known for its role in CC. RNA expression analysis showed no significant difference in PAX6 transcript levels between affected individuals and healthy controls. However, luciferase reporter assays demonstrated that the PAX6 variant protein exhibited significantly increased reporter activity compared to the wild-type protein. These findings indicate that the phenotypic spectrum of PAX6 may extend to include SPG, as observed in this single family, potentially through altered transcriptional activity.