Expandingthe Phenotypic Spectrum of PUS3 Deficiency: A p.Tyr71Cys Case Demonstrating a Stable, Nonprogressive...

PUS3 encodes a transfer RNA (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.

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, nonprogressive, 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).

This first reported PUS3-deficient patient from Turkey - and the fifth globally with p.Tyr71Cys - demonstrates a nonprogressive, 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.