A Homozygous c.74A>G Variant in PRKRA Causes DYT‐PRKRA: Extensive Familial Segregation and a Variant of Uncertain Significance (VUS) Reclassification

Background DYT‐PRKRA is a rare, autosomal recessive movement disorder caused by mutations in the PRKRA gene. While PRKRA mutations are recognized in DYT‐PRKRA, a significant number of identified variants are still classified as “variant of uncertain significance” (VUS). Objective In this study we identified a causative variant previously reported as a VUS. Methods A 4.5‐year‐old female born to consanguineous, healthy parents presented with progressive neurodevelopmental regression, similar to two affected relatives. Whole‐exome sequencing was performed, and segregation analysis was conducted across two generations. Results A homozygous PRKRA c.74A>G (p.Lys25Arg) variant co‐segregated with the DYT‐PRKRA phenotype. Unaffected family members were identified as heterozygous carriers. Conclusions This is the first report of DYT‐PRKRA in the Iranian population. Strong evidence from familial segregation and in silico analyses support the reclassification of this variant to likely pathogenic. This reclassification has significant implications for the diagnosis and genetic counseling of families affected by DYT‐PRKRA.