Disruption of RFX family transcription factors causes autism, attention deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior

ABSTRACT Purpose We describe a novel neurobehavioral syndrome of autism spectrum disorder, intellectual disability, and attention deficit/hyperactivity disorder associated with de novo or inherited deleterious variants in members of the RFX family of genes. RFX genes are evolutionarily conserved transcription factors that act as master regulators of central nervous system development and ciliogenesis. Methods We assembled a cohort of 36 individuals (from 31 unrelated families) with de novo mutations in RFX3, RFX4 , and RFX7 . We describe their common clinical phenotypes and present bioinformatic analyses of expression patterns and downstream targets of these genes as they relate to other neurodevelopmental risk genes. Results These individuals share neurobehavioral features including autism spectrum disorder (ASD), intellectual disability, and attention-deficit/hyperactivity disorder (ADHD); other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4 , and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. Conclusion These results establish deleterious variation in RFX3, RFX4 , and RFX7 as important causes of monogenic intellectual disability, ADHD and ASD, and position these genes as potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.