Holly K Harris1,2, Tojo Nakayama3,4, Jenny Lai3,5, Boxun Zhao3,4, Nikoleta Argyrou3,4, Cynthia S Gubbels3,4, Aubrie Soucy3,4, Casie A Genetti3,4, Victoria Suslovitch3,4, Lance H Rodan3,4,6, George E Tiller7, Gaetan Lesca8, Karen W Gripp9, Reza Asadollahi10, Ada Hamosh11, Carolyn D Applegate11, Peter D Turnpenny12, Marleen E H Simon13, Catharina M L Volker-Touw13, Koen L I van Gassen13, Ellen van Binsbergen13, Rolph Pfundt14, Thatjana Gardeitchik14, Bert B A de Vries14, LaDonna L Immken15, Catherine Buchanan15, Marcia Willing16, Tomi L Toler16, Emily Fassi16, Laura Baker9, Fleur Vansenne17, Xiadong Wang18, Julian L Ambrus19, Madeleine Fannemel20, Jennifer E Posey21, Emanuele Agolini22, Antonio Novelli22, Anita Rauch10, Paranchai Boonsawat10, Christina R Fagerberg23, Martin J Larsen23, Maria Kibaek23, Audrey Labalme8, Alice Poisson8, Katelyn K Payne24, Laurence E Walsh24,25, Kimberly A Aldinger26, Jorune Balciuniene27, Cara Skraban27, Christopher Gray27, Jill Murrell27, Caleb P Bupp28, Giulia Pascolini29, Paola Grammatico29, Martin Broly30, Sébastien Küry30, Mathilde Nizon30, Iqra Ghulam Rasool31,32, Muhammad Yasir Zahoor31, Cornelia Kraus32, André Reis32, Muhammad Iqbal33, Kevin Uguen34,35, Severine Audebert-Bellanger34, Claude Ferec34,35, Sylvia Redon34,35, Janice Baker36, Yunhong Wu37, Guiseppe Zampino38, Steffan Syrbe39, Ines Brosse39, Rami Abou Jamra40, William B Dobyns41, Lilian L Cohen42, Anne Blomhoff20, Cyril Mignot43,44, Boris Keren43, Thomas Courtin43, Pankaj B Agrawal3,4, Alan H Beggs3,4, Timothy W Yu45,46,47. 1. Division of Developmental Medicine, Department of Medicine, Boston Children's Hospital, Boston, MA, USA. 2. Department of Pediatrics, Baylor College of Medicine and Meyer Center for Developmental Pediatrics, Texas Children's Hospital, Houston, TX, USA. 3. Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA. 4. The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA. 5. Program in Neuroscience, Harvard University, Boston, MA, USA. 6. Department of Neurology, Boston Children's Hospital, Boston, MA, USA. 7. Department of Genetics, Kaiser Permanente, Los Angeles, CA, USA. 8. Department of Medical Genetics, Lyon University Hospital, Bron, France. 9. Division of Medical Genetics, Nemours/A.I. DuPont Hospital for Children, Wilmington, DE, USA. 10. Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland. 11. Department of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA. 12. Peninsula Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK. 13. Department of Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands. 14. Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands. 15. Dell Children's Medical Group, Department of Clinical and Metabolic Genetics, Austin, TX, USA. 16. Division of Genetics and Genomic Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, USA. 17. Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands. 18. Ciphergene, Beijing, China. 19. Division of Allergy, Immunology, and Rheumatology, SUNY at Buffalo School of Medicine, Buffalo, NY, USA. 20. Department of Medical Genetics, Oslo University Hospital, Oslo, Norway. 21. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. 22. Laboratory of Medical Genetics, Bambino Gesu Children's Hospital, Rome, Italy. 23. Department of Clinical Genetics, Odense University Hospital, Odense, Denmark. 24. Department of Neurology, Indiana University Health Neuroscience Center, Indianapolis, IN, USA. 25. Department of Medical and Molecular Genetics, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA. 26. Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA. 27. Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. 28. Spectrum Health Helen DeVos Children's Hospital, Grand Rapids, MI, USA. 29. Laboratory of Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Roma, Italy. 30. CHU Nantes, Service de Génétique Médicale, Nantes, France; L'institut du thorax, INSERM, CNRS, UNIV Nantes, CHU Nantes, Nantes, France. 31. Institute of Biochemistry & Biotechnology, University of Veterinary & Animal Sciences, Lahore, Pakistan. 32. Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany. 33. Department of Biochemistry and Biotechnology, The Islamia University of Bahawalpur, Punjab, Pakistan. 34. Department of Medical Genetics, Brest University Hospital, Brest, France. 35. Univ Brest, Inserm, EFS, UMR 1078, GGB, Brest, France. 36. Department of Genomic Medicine, Children's Minnesota, Minneapolis, MN, USA. 37. Shanxi Children's Hospital, Taiyuan, China. 38. Center for Rare Disease and Congenital Defects, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Universita Cattolica del Sacro Cuore, Rome, Italy. 39. Division of Pediatric Epileptology, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany. 40. Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany. 41. Departments of Pediatrics and Genetics, University of Minnesota, Minneapolis, MN, USA. 42. Division of Medical Genetics, Weill Cornell Medical College, New York, NY, USA. 43. APHP.Sorbonne Université, Département de Génétique, Groupe Hospitalier Pitié-Salpêtrière, Paris, France. 44. Centre de Référence Déficiences Intellectuelles de Causes Rares, Paris, France. 45. Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA. timothy.yu@childrens.harvard.edu. 46. The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA. timothy.yu@childrens.harvard.edu. 47. Program in Neuroscience, Harvard University, Boston, MA, USA. timothy.yu@childrens.harvard.edu.
Abstract
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.
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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