Several neurodevelopmental disorders, including autism, have been linked to the aberrant development of γ-aminobutyric acid (GABA)-expressing interneurons in the mammalian forebrain. Dlx homeobox genes control the development of these interneurons and now, on p. 3089, Marc Ekker and colleagues report that a rare, autism-associated single-nucleotide polymorphism (SNP) in an ultraconserved regulatory element (I56i) in the DLX5/DLX6 bigene cluster affects Dlx5/Dlx6 regulation in the mouse forebrain. The researchers show that the SNP, which lies in a functional protein binding site, reduces I56i enhancer activity in the developing mouse forebrain and in adult GABAergic interneurons. Notably, Dlx proteins have a reduced affinity for the variant I56i protein binding site in vitro, they report, which reduces the transcriptional activation of the enhancer by Dlx. The researchers propose, therefore, that impaired I56i enhancer activity by the SNP could affect the auto- or cross-regulation of the DLX5/DLX6 bigene cluster, thereby disrupting cortical interneuron development and contributing to the developmental abnormalities that underlie autism.