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

Harris HK, Nakayama T, Lai J, Zhao B, Argyrou N, Gubbels CS, Soucy A, Genetti CA, Suslovitch V, Rodan LH, Tiller GE, Lesca G, Gripp KW, Asadollahi R, Hamosh A, Applegate CD, Turnpenny PD, Simon MEH, Volker-Touw CML, Gassen KLIV, Binsbergen EV, Pfundt R, Gardeitchik T, Vries BBAD, Immken LL, Buchanan C, Willing M, Toler TL, Fassi E, Baker L, Vansenne F, Wang X, Ambrus JL, Fannemel M, Posey JE, Agolini E, Novelli A, Rauch A, Boonsawat P, Fagerberg CR, Larsen MJ, Kibaek M, Labalme A, Poisson A, Payne KK, Walsh LE, Aldinger KA, Balciuniene J, Skraban C, Gray C, Murrell J, Bupp CP, Pascolini G, Grammatico P, Broly M, Kury S, Nizon M, Rasool IG, Zahoor MY, Kraus C, Reis A, Iqbal M, Uguen K, Audebert-Bellanger S, Ferec C, Redon S, Baker J, Wu Y, Zampino G, Syrbe S, Brosse I, Jamra RA, Dobyns WB, Cohen LL, Blomhoff A, Mignot C, Keren B, Courtin T, Agrawal PB, Beggs AH, Yu TW (2021)

Publication Type: Journal article

Publication year: 2021


DOI: 10.1038/s41436-021-01114-z


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.

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Involved external institutions

University Medical Centre Utrecht (UMC Utrecht) NL Netherlands (NL) Children's Hospitals and Clinics of Minnesota US United States (USA) (US) Children's Hospital of Philadelphia US United States (USA) (US) Università degli studi "La Sapienza" IT Italy (IT) University of Veterinary and Animal Sciences (UVAS) PK Pakistan (PK) University of Paris 4 - Paris-Sorbonne / Université paris IV Paris-Sorbonne FR France (FR) Université de Bretagne Occidentale FR France (FR) Odense Universitetshospital (OUH) DK Denmark (DK) Lyon University Hospital FR France (FR) Université de Nantes FR France (FR) Indiana University US United States (USA) (US) Universität Leipzig DE Germany (DE) University of Minnesota (UMN) US United States (USA) (US) Islamia University of Bahawalpur (IUB) / اسلامیہ یونیورسٹی بہاولپور PK Pakistan (PK) Universitätsklinikum Heidelberg DE Germany (DE) Shanxi Provincial Children's Hospital / 山西省妇幼保健院 CN China (CN) Boston Children's Hospital US United States (USA) (US) Oslo University Hospital / Oslo Universitetssykehus Rikshospitalet NO Norway (NO) University of Zurich / Universität Zürich (UZH) CH Switzerland (CH) Cornell University US United States (USA) (US) Seattle Children's Hospital US United States (USA) (US) University at Buffalo. State University of New York US United States (USA) (US) Houston Texas Medical Center US United States (USA) (US) University Medical Center Groningen (UMCG) / Universitair Medisch Centrum Groningen NL Netherlands (NL) Catholic University of the Sacred Heart / Università Cattolica del Sacro Cuore IT Italy (IT) Radboud University Nijmegen NL Netherlands (NL) Ospedale Pediatrico Bambino Gesu IT Italy (IT) Washington University in St. Louis US United States (USA) (US) Nemours/Alfred I. duPont Hospital for Children US United States (USA) (US) Dell Children's Medical Center of Central Texas US United States (USA) (US) Johns Hopkins University (JHU) US United States (USA) (US) Royal Devon & Exeter NHS Foundation Trust GB United Kingdom (GB) Spectrum Health US United States (USA) (US) Kaiser Permanente US United States (USA) (US)

How to cite


Harris, H.K., Nakayama, T., Lai, J., Zhao, B., Argyrou, N., Gubbels, C.S.,... Yu, T.W. (2021). Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior. Genetics in Medicine. https://doi.org/10.1038/s41436-021-01114-z


Harris, Holly K., et al. "Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior." Genetics in Medicine (2021).

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