Background: PUS3 encodes a tRNA pseudouridine synthase essential for translational fidelity. Biallelic pathogenic variants cause a rare autosomal recessive neurodevelopmental disorder characterized by intellectual disability, microcephaly, hypotonia, and gray sclera. Fewer than thirty individuals have been reported, including only five carrying the recurrent c.212A>G (p.Tyr71Cys) variant. Case Presentation: We describe a 17-year-old girl born to second-degree consanguineous parents presenting with lifelong global developmental delay, microcephaly, gray sclera, dysmorphic features, and intellectual disability. Neurological examination revealed hyporeflexia without seizures. Brain MRI demonstrated stable, non-progressive, linear–nodular T2 hyperintense lesions confined to the subcortical white matter with a normal corpus callosum, an imaging pattern rarely associated with PUS3 deficiency. Whole-exome sequencing identified a homozygous PUS3 c.212A>G (p.Tyr71Cys) variant, classified as likely pathogenic based on ACMG criteria (PM2, PM3, PP3, PP5). Conclusion: This first reported PUS3-deficient patient from Turkey—and the fifth globally with p.Tyr71Cys—demonstrates a non-progressive, radiologically silent white-matter phenotype in the absence of epilepsy or callosal abnormalities. Her stable neurological course into late adolescence broadens the phenotypic spectrum of PUS3 deficiency and underscores the need for long-term clinical monitoring in disorders of tRNA modification.
Aygün et al. (Thu,) studied this question.