ArticleGenetics in medicine : official journal of the American College of Medical Genetics2021
Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior.
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Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers, 1 of them a synthesis that pooled it.
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56 citing papers in PubMed, 1 synthesis or guideline pooled it, 83 citations in OpenAlex.
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- Epidemiological characteristics of comorbidities in childhood Attention-Deficit/Hyperactivity Disorder and common comorbidity patterns.Frontiers in public health · 2026Article
- Large-scale discovery of neural enhancers for cis-regulation therapies.bioRxiv : the preprint server for biology · 2025Article
- Epigenomic landscape of the developing human rhombic lip reveals gene regulatory network and non-coding loci of developmental, evolutionary, and disease relevance.bioRxiv : the preprint server for biology · 2025Article
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Authors and funding
81 authors at 20 institutions in 11 countries.
Holly K Harris *Division of Developmental Medicine, Department of Medicine, Boston Children's Hospital, Boston, MA, USA.
Tojo Nakayama *Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
Jenny Lai *Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
Boxun ZhaoDivision of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
Nikoleta ArgyrouDivision of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
Cynthia S GubbelsDivision of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
Aubrie SoucyDivision of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
Casie A GenettiDivision of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
Victoria SuslovitchDivision of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
Lance H RodanDivision of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
George E TillerDepartment of Genetics, Kaiser Permanente, Los Angeles, CA, USA.
Gaetan LescaDepartment of Medical Genetics, Lyon University Hospital, Bron, France.
Karen W GrippDivision of Medical Genetics, Nemours/A.I. DuPont Hospital for Children, Wilmington, DE, USA.
Reza AsadollahiInstitute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland.
Ada HamoshDepartment of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA.
Carolyn D ApplegateDepartment of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA.
Peter D TurnpennyPeninsula Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
Marleen E H SimonDepartment of Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands.
Catharina M L Volker-TouwDepartment of Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands.
Koen L I van GassenDepartment of Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands.
Ellen van BinsbergenDepartment of Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands.
Rolph PfundtDepartment of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
Thatjana GardeitchikDepartment of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
Bert B A de VriesDepartment of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
LaDonna L ImmkenDell Children's Medical Group, Department of Clinical and Metabolic Genetics, Austin, TX, USA.
Catherine BuchananDell Children's Medical Group, Department of Clinical and Metabolic Genetics, Austin, TX, USA.
Marcia WillingDivision of Genetics and Genomic Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
Tomi L TolerDivision of Genetics and Genomic Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
Emily FassiDivision of Genetics and Genomic Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
Laura BakerDivision of Medical Genetics, Nemours/A.I. DuPont Hospital for Children, Wilmington, DE, USA.
Fleur VansenneDepartment of Genetics, University Medical Center Groningen, Groningen, The Netherlands.
Xiadong WangCiphergene, Beijing, China.
Julian L AmbrusDivision of Allergy, Immunology, and Rheumatology, SUNY at Buffalo School of Medicine, Buffalo, NY, USA.
Madeleine FannemelDepartment of Medical Genetics, Oslo University Hospital, Oslo, Norway.
Jennifer E PoseyDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Emanuele AgoliniLaboratory of Medical Genetics, Bambino Gesu Children's Hospital, Rome, Italy.
Antonio NovelliLaboratory of Medical Genetics, Bambino Gesu Children's Hospital, Rome, Italy.
Anita RauchInstitute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland.
Paranchai BoonsawatInstitute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland.
Christina R FagerbergDepartment of Clinical Genetics, Odense University Hospital, Odense, Denmark.
Martin J LarsenDepartment of Clinical Genetics, Odense University Hospital, Odense, Denmark.
Maria KibaekDepartment of Clinical Genetics, Odense University Hospital, Odense, Denmark.
Audrey LabalmeDepartment of Medical Genetics, Lyon University Hospital, Bron, France.
Alice PoissonDepartment of Medical Genetics, Lyon University Hospital, Bron, France.
Katelyn K PayneDepartment of Neurology, Indiana University Health Neuroscience Center, Indianapolis, IN, USA.
Laurence E WalshDepartment of Neurology, Indiana University Health Neuroscience Center, Indianapolis, IN, USA.
Kimberly A AldingerCenter for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.
Jorune BalciunieneDivision of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Cara SkrabanDivision of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Christopher GrayDivision of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Jill MurrellDivision of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Caleb P BuppSpectrum Health Helen DeVos Children's Hospital, Grand Rapids, MI, USA.
Giulia PascoliniLaboratory of Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Roma, Italy.
Paola GrammaticoLaboratory of Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Roma, Italy.
Martin BrolyCHU Nantes, Service de Génétique Médicale, Nantes, France; L'institut du thorax, INSERM, CNRS, UNIV Nantes, CHU Nantes, Nantes, France.
Sébastien KüryCHU Nantes, Service de Génétique Médicale, Nantes, France; L'institut du thorax, INSERM, CNRS, UNIV Nantes, CHU Nantes, Nantes, France.
Mathilde NizonCHU Nantes, Service de Génétique Médicale, Nantes, France; L'institut du thorax, INSERM, CNRS, UNIV Nantes, CHU Nantes, Nantes, France.
Iqra Ghulam RasoolInstitute of Biochemistry & Biotechnology, University of Veterinary & Animal Sciences, Lahore, Pakistan.
Muhammad Yasir ZahoorInstitute of Biochemistry & Biotechnology, University of Veterinary & Animal Sciences, Lahore, Pakistan.
Cornelia KrausInstitute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany.
André ReisInstitute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany.
Muhammad IqbalDepartment of Biochemistry and Biotechnology, The Islamia University of Bahawalpur, Punjab, Pakistan.
Kevin UguenDepartment of Medical Genetics, Brest University Hospital, Brest, France.
Severine Audebert-BellangerDepartment of Medical Genetics, Brest University Hospital, Brest, France.
Claude FerecDepartment of Medical Genetics, Brest University Hospital, Brest, France.
Sylvia RedonDepartment of Medical Genetics, Brest University Hospital, Brest, France.
Janice BakerDepartment of Genomic Medicine, Children's Minnesota, Minneapolis, MN, USA.
Yunhong WuShanxi Children's Hospital, Taiyuan, China.
Guiseppe ZampinoCenter for Rare Disease and Congenital Defects, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Universita Cattolica del Sacro Cuore, Rome, Italy.
Steffan SyrbeDivision of Pediatric Epileptology, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
Ines BrosseDivision of Pediatric Epileptology, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
Rami Abou JamraInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
William B DobynsDepartments of Pediatrics and Genetics, University of Minnesota, Minneapolis, MN, USA.
Lilian L CohenDivision of Medical Genetics, Weill Cornell Medical College, New York, NY, USA.
Anne BlomhoffDepartment of Medical Genetics, Oslo University Hospital, Oslo, Norway.
Cyril MignotAPHP.Sorbonne Université, Département de Génétique, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
Boris KerenAPHP.Sorbonne Université, Département de Génétique, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
Thomas CourtinAPHP.Sorbonne Université, Département de Génétique, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
Pankaj B AgrawalDivision of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
Alan H BeggsDivision of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
Timothy W YuDivision of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA. timothy.yu@childrens.harvard.edu.ORCID http://orcid.org/0000-0003-2988-7701
Boston Children's Hospital · USChildren's Hospital of Philadelphia · USUniversity Medical Center Utrecht · NLCentre National de la Recherche Scientifique · FRFriedrich-Alexander-Universität Erlangen-Nürnberg · DEHospices Civils de Lyon · FRInserm · FROdense University Hospital · DKRadboud University Nijmegen · NLSorbonne Université · FRUniversity of Zurich · CHWashington University in St. Louis · USBambino Gesù Children's Hospital · ITCarlo Forlanini Hospital · ITDell Children's Medical Center of Central Texas · USDuPont (United States) · USHeidelberg University · DEIndiana University Health · USJohns Hopkins University · USOslo University Hospital · NO
Funding
Medical Scientist Training ProgramT32GM007753 · NIGMS · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI WALENSKY, LOREN DAVID · 1985 to 2021
$50.0MBaylor-Johns Hopkins Center for Mendelian GeneticsUM1HG006542 · NHGRI · JOHNS HOPKINS UNIVERSITY · PI VALLE, DAVID · 2016 to 2020
$14.5MGenome Sequence-Based Screening for Childhood Risk and Newborn IllnessU19HD077671 · NICHD · BRIGHAM AND WOMEN'S HOSPITAL · PI BEGGS, ALAN H., GREEN, ROBERT C. · 2013 to 2018
$6.1MComplete gene knockouts in autism: identification and functional characterizationR01MH113761 · NIMH · BOSTON CHILDREN'S HOSPITAL · PI YU, TIMOTHY WEI-WEN · 2017 to 2021
$2.2MExpert Panel: Genetics of Malformations of the Central Nervous SystemU24HD093487 · NICHD · BOSTON CHILDREN'S HOSPITAL · PI PODURI, ANNAPURNA, YU, TIMOTHY WEI-WEN · 2017 to 2019
$988kDepartment of Health HICF-1009-003NHGRI NIH HHS UM1 HG006542NICHD NIH HHS U19 HD077671NICHD NIH HHS U24 HD093487NIGMS NIH HHS T32 GM007753NIMH NIH HHS R01 MH113761Wellcome TrustWellcome Trust WT098051
Abstract
purposeWe 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.
methodsWe 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.
resultsThese 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.
conclusionThese 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.
Indexed as
Attention Deficit Disorder with HyperactivityAutism Spectrum DisorderAutistic DisorderIntellectual DisabilityAdultHumansRegulatory Factor X Transcription FactorsTranscription FactorsRegulatory Factor X Transcription FactorsRFX3 protein, humanRFX4 protein, humanRFX7 protein, humanTranscription Factors
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