A Novel TAF1C Missense Variant Causes Neurodevelopmental Regression via Disrupted Nucleolar Localization and Nucleoplasmic Aggregation

ABSTRACT TAF1C (TATA box‐binding protein‐associated factor, RNA polymerase I subunit C) is an essential component of the RNA polymerase I transcription machinery responsible for ribosomal RNA synthesis and nucleolar function. Variants in TAF1C have recently emerged as rare genetic causes of early‐onset neurological syndromes characterized by nucleolar stress and impaired ribosome biogenesis, leading to developmental delay and brain atrophy. Here, we report a novel homozygous missense variant (c.1766C>T; p.Ser589Leu) in TAF1C in a 3‐year 8‐month‐old boy who exhibited normal development until age two, followed by generalized seizures and progressive neurodevelopmental regression, spasticity, microcephaly, and cerebellar atrophy. MRI revealed asymmetric diffusion restriction and diffuse cerebellar atrophy. Although the mutant TAF1C transcript and protein were expressed at normal levels in peripheral blood cells, immunofluorescence analysis revealed a loss of nucleolar localization and the formation of abnormal thread‐like aggregates within the nucleoplasm. These findings suggest that the p.Ser589Leu variant causes disease through functional mislocalization rather than loss of expression. Our case expands the phenotypic and mechanistic spectrum of TAF1C ‐related disorders and highlights the importance of proper subnuclear localization for maintaining neuronal function and development.