Here we have identified a common unifying cellular and biochemical mechanism underpinning the pathogenesis of TCS irrespective of whether its cause is associated with mutations in TCOF1, POLR1C, or POLR1D. Mutations in TCOF1 account for about 80% of patients with TCS, while mutations in POLR1C and POLR1D account for only about 2% of the patients sequenced to date. Here, POLR1C is linked to Treacher-Collins syndrome.