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

Holly K. Harris, Tojo Nakayama, Jenny Lai, Boxun Zhao, Nikoleta Argyrou, Cynthia S. Gubbels, Aubrie Soucy, Casie A. Genetti, Victoria Suslovitch, Lance H. Rodan, George E. Tiller, Gaetan Lesca, Karen W. Gripp, Reza Asadollahi, Ada Hamosh, Carolyn D. Applegate, Peter D. Turnpenny, Marleen E.H. Simon, Catharina M.L. Volker-Touw, Koen L.I.van GassenEllen van Binsbergen, Rolph Pfundt, Thatjana Gardeitchik, Bert B.A.de Vries, La Donna L. Immken, Catherine Buchanan, Marcia Willing, Tomi L. Toler, Emily Fassi, Laura Baker, Fleur Vansenne, Xiadong Wang, Julian L. Ambrus, Madeleine Fannemel, Jennifer E. Posey, Emanuele Agolini, Antonio Novelli, Anita Rauch, Paranchai Boonsawat, Christina R. Fagerberg, Martin J. Larsen, Maria Kibaek, Audrey Labalme, Alice Poisson, Katelyn K. Payne, Laurence E. Walsh, Kimberly A. Aldinger, Jorune Balciuniene, Cara Skraban, Christopher Gray, Jill Murrell, Caleb P. Bupp, Giulia Pascolini, Paola Grammatico, Martin Broly, Sébastien Küry, Mathilde Nizon, Iqra Ghulam Rasool, Muhammad Yasir Zahoor, Cornelia Kraus, André Reis, Muhammad Iqbal, Kevin Uguen, Severine Audebert-Bellanger, Claude Ferec, Sylvia Redon, Janice Baker, Yunhong Wu, Guiseppe Zampino, Steffan Syrbe, Ines Brosse, Rami Abou Jamra, William B. Dobyns, Lilian L. Cohen, Anne Blomhoff, Cyril Mignot, Boris Keren, Thomas Courtin, Pankaj B. Agrawal, Alan H. Beggs, Timothy W. Yu

Research output: Contribution to journalArticlepeer-review


Purpose: We describe a novel neurobehavioral phenotype of autism spectrum disorder (ASD), intellectual disability, and/or attention-deficit/hyperactivity disorder (ADHD) 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 38 individuals (from 33 unrelated families) with de novo variants 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 ASD, intellectual disability, and/or 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 a likely role of deleterious variation in RFX3, RFX4, and RFX7 in cases of monogenic intellectual disability, ADHD and ASD, and position these genes as potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.

Original languageEnglish (US)
Pages (from-to)1028-1040
Number of pages13
JournalGenetics in Medicine
Issue number6
StatePublished - Jun 2021

ASJC Scopus subject areas

  • Genetics(clinical)


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