TBLR1, a subunit of the NCoR corepressor complex, is mutated in a range of neurodevelopmental disorders that only partially align symptomatically with those caused by mutations in its binding partner, MeCP2. In a search for novel TBLR1-binding partners, we identified ANKRD11 and SETD5 – mutations in which are amongst the most frequent genetic causes of neurodevelopmental disorders. Here we report that TBLR1 provides a molecular bridge between ANKRD11, SETD5 and NCoR in a complex with a strikingly resembles the SET3C complex of yeast. Pathogenic missense mutations in TBLR1, ANKRD11 and SETD5 disrupt this mammalian SET3C-like assembly. Mutations of this kind in Ankrd11 and Setd5 genes cause highly correlated changes in gene expression and severe developmental impairments. We present evidence that this complex restrains the expression of highly transcribed genes. Our results demonstrate that failure of transcriptional regulation by SET3C provides a convergent molecular basis for a family of neurodevelopmental disorders.