POLR1C encodes a core subunit of RNA polymerase I and III, essential enzymes that transcribe different classes of non-coding RNAs. 1 POLR1C functions as a structural component within the polymerase core, possibly acting as a clamp element regulating the enzyme's catalytic cleft. 1 As a shared subunit between Pol I and Pol III, POLR1C participates in transcribing ribosomal RNA precursors and transfer RNAs, respectively, making it critical for ribosome biogenesis and protein synthesis. Mutations in POLR1C cause two clinically distinct disorders: Treacher Collins syndrome (TCS) type 3 and hypomyelinating leukodystrophy (4H leukodystrophy). 2 TCS presents with craniofacial abnormalities including microtia, midface hypoplasia, and micrognathia, affecting approximately 1 in 50,000 live births. 2 Disease pathogenesis involves impaired ribosomal RNA synthesis in neural crest cells, leading to p53 accumulation and apoptosis. 3 4 In 4H leukodystrophy, biallelic POLR1C variants cause hypomyelination, hypodontia, and hypogonadotropic hypogonadism, with additional endocrine complications including delayed puberty (77% of cases) and short stature (61%). 5 6 The pleiotropic effects reflect POLR1C's widespread requirement for RNA synthesis across multiple developing tissues, particularly those with high protein synthesis demands.