ArticleAmerican journal of human genetics2015
Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling.
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In one paragraph
Article in American journal of human genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 177 papers, 2 of them syntheses that pooled it.
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177citing papers in PubMed, 2 pooled it
15.1field-weighted citation impact, top 1% of its field
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Who cites it
177 citing papers in PubMed, 2 syntheses or guidelines pooled it, 330 citations in OpenAlex.
- Communicative Development Inventories (CDIs) in etiologically diverse developmental conditions: A systematic review.Research in developmental disabilities · 2026Pooled it
- Connecting DCX, COMT and FMR1 in social behavior and cognitive impairment.Behavioral and brain functions : BBF · 2022Pooled it
- Genome sequencing for the diagnosis of intellectual disability as a paradigm for rare diseases in the French healthcare setting: the prospective DEFIDIAG study.Genome medicine · 2025Trial
- Using Solution NMR to Study the RNA-Binding Properties and Molecular Mechanisms of the RNA Helicase DDX3X.Methods in molecular biology (Clifton, N.J.) · 2027Article
- The Great Escape: A Case Series onThe Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association · 2026Article
- Identification of highly immunogenic endogenous dsRNAs from cellular MDA5 filaments.bioRxiv : the preprint server for biology · 2026Article
- Long-read genome sequencing improves detection and functional interpretation of structural and repeat variants in autism.Cell genomics · 2026Article
- Modeling rare coding variation on chromosome X provides insight into the genetics and differential sex prevalence of autism spectrum disorder.medRxiv : the preprint server for health sciences · 2026Article
- DDX3X Syndrome: Clinical, Neuroimaging, AI-Assisted Facial Profiling and Genotype-Phenotype Correlations.Genes · 2026Observational
- Sex-aware genome-wide assessment of de novo variants in autism across coding and noncoding regions.Human genomics · 2026Article
- Knockdown of Ddx3x in mPFC induces autistic-like phenotype in mice via altered synaptic plasticity.Translational psychiatry · 2026Article
- Article
- Resolving Diagnostic Uncertainty in Neurodevelopmental Disorders Using Exome Sequencing Supported by Literature-Based Multi-Omics Evidence.Biomolecules · 2026Article
- De Novo Variation in Autism by Sex and Diagnostic Status in 41,367 Parent-Child Trios.medRxiv : the preprint server for health sciences · 2026Article
- Evaluation of the contribution of trio-exome sequencing in selected prenatal indications.Frontiers in genetics · 2026Article
- Approaches for identification of 5' UTR mutations impacting translation and protein production from neurodevelopmental disorder genes.Cell reports methods · 2025Article
- Impaired cortical development and translational control in a missense mouse model of DDX3X syndrome.Disease models & mechanisms · 2025Article
- Exploration of a DDX3X Gene Supplementation Therapy Including Expanded Characterization and Novel Findings of Sleep Disturbances inBiological psychiatry global open science · 2025Article
- Using Whole Exome Sequencing to Identify Genetic Causes of Neurodevelopmental Disorders in a Cohort of 11 Patients: A Single Center Experience.International journal of molecular sciences · 2025Article
- The inactive X chromosome as a female protector in autism and beyond.Research square · 2025Article
117 more citing papers are in PubMed but not listed here.
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Authors and funding
86 authors at 20 institutions in 8 countries.
Lot Snijders BlokDepartment of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
Erik MadsenCenter for Human Disease Modeling, Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
Jane JuusolaGeneDx, Gaithersburg, MD 20877, USA.
Christian GilissenDepartment of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
Diana BaralleHuman Development and Health, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
Margot R F ReijndersDepartment of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
Hanka VenselaarNijmegen Centre for Molecular and Biomolecular Informatics, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
Céline HelsmoortelDepartment of Medical Genetics, University of Antwerp and University Hospital Antwerp, 2650 Antwerp, Belgium.
Megan T ChoGeneDx, Gaithersburg, MD 20877, USA.
Alexander HoischenDepartment of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
Lisenka E L M VissersDepartment of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
Tom S KoemansDepartment of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
Willemijn Wissink-LindhoutDepartment of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
Evan E EichlerDepartment of Genome Sciences, University of Washington, Seattle, WA 98195-5065, USA; Howard Hughes Medical Institute, Seattle, WA 98195, USA.
Corrado RomanoPediatrics and Medical Genetics, IRCCS Associazione Oasi Maria Santissima, 94018 Troina, Italy.
Hilde Van EschCenter for Human Genetics, University Hospitals Leuven, 3000 Leuven, Belgium.
Connie StumpelDepartment of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht UMC+, 6202 AZ Maastricht, the Netherlands.
Maaike VreeburgDepartment of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht UMC+, 6202 AZ Maastricht, the Netherlands.
Eric SmeetsDepartment of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht UMC+, 6202 AZ Maastricht, the Netherlands.
Karin OberndorffDepartment of Pediatrics, Atrium-Orbis Medical Center, 6162 BG Sittard, the Netherlands.
Bregje W M van BonDepartment of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; School of Paediatrics and Reproductive Health and Robinson Research Institute, The University of Adelaide, Adelaide, SA 5006, Australia.
Marie ShawSchool of Paediatrics and Reproductive Health and Robinson Research Institute, The University of Adelaide, Adelaide, SA 5006, Australia.
Jozef GeczSchool of Paediatrics and Reproductive Health and Robinson Research Institute, The University of Adelaide, Adelaide, SA 5006, Australia.
Eric HaanSchool of Paediatrics and Reproductive Health and Robinson Research Institute, The University of Adelaide, Adelaide, SA 5006, Australia; South Australian Clinical Genetics Service, SA Pathology, Adelaide, SA 5006, Australia.
Melanie BienekDepartment of Human Genetics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
Corinna JensenDepartment of Human Genetics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
Bart L LoeysDepartment of Medical Genetics, University of Antwerp and University Hospital Antwerp, 2650 Antwerp, Belgium.
Anke Van DijckDepartment of Medical Genetics, University of Antwerp and University Hospital Antwerp, 2650 Antwerp, Belgium.
A Micheil InnesDepartment of Medical Genetics and Alberta Children's Hospital Research Institute for Child and Maternal Health, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
Hilary RacherDepartment of Medical Genetics and Alberta Children's Hospital Research Institute for Child and Maternal Health, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
Sascha VermeerDepartment of Genetics, University Medical Center Groningen, 9700 RB Groningen, the Netherlands.
Nataliya Di DonatoFaculty of Medicine, Carl Gustav Carus TU Dresden, 01307 Dresden, Germany.
Andreas RumpFaculty of Medicine, Carl Gustav Carus TU Dresden, 01307 Dresden, Germany.
Katrina Tatton-BrownSt George's University of London, London SW17 0RE, UK.
Michael J ParkerSheffield Clinical Genetics Service, Sheffield Children's Hospital, Western Bank, Sheffield S10 2TH, UK.
Alex HendersonNorthern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 3BZ, UK.
Sally A LynchNational Centre for Medical Genetics, Temple Street Children's Hospital, Crumlin, Dublin 12, Ireland.
Alan FryerDepartment of Clinical Genetics, Liverpool Women's Hospital and Alder Hey Children's Hospital, Liverpool L8 7SS, UK.
Alison RossNorth of Scotland Regional Genetics Service, Clinical Genetics Centre, Aberdeen AB25 2ZA, UK.
Pradeep VasudevanDepartment of Clinical Genetics, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester LE1 5WW, UK.
Usha KiniDepartment of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford OX3 7LE, UK.
Ruth Newbury-EcobDepartment of Clinical Genetics, University Hospitals, Bristol BS1 3NU, UK.
Kate ChandlerManchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), Manchester M13 9WL, UK.
Alison MaleNorth East Thames Regional Genetics Service, Great Ormond Street Hospital, Great Ormond Street, London WC1N 3JH, UK.
DDD Study
Sybe DijkstraORO, Organisation for People with Intellectual Disabilities, 5751 PH Deurne, the Netherlands.
Jolanda SchievingDepartment of Child Neurology, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
Jacques GiltayDepartment of Medical Genetics, University Medical Center Utrecht, 3508 AB Utrecht, the Netherlands.
Koen L I van GassenDepartment of Medical Genetics, University Medical Center Utrecht, 3508 AB Utrecht, the Netherlands.
Janneke Schuurs-HoeijmakersDepartment of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
Perciliz L TanCenter for Human Disease Modeling, Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
Igor PediaditakisCenter for Human Disease Modeling, Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
Stefan A HaasDepartment of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
Kyle RettererGeneDx, Gaithersburg, MD 20877, USA.
Patrick ReedGeneDx, Gaithersburg, MD 20877, USA.
Kristin G MonaghanGeneDx, Gaithersburg, MD 20877, USA.
Eden HaverfieldGeneDx, Gaithersburg, MD 20877, USA.
Marvin NatowiczPathology & Laboratory Medicine and Genomic Medicine Institutes, Cleveland Clinic, Cleveland, OH 44195, USA.
Angela MyersSanford Children's Specialty Clinic, Sioux Falls, SD 57105, USA.
Michael C KruerSanford Children's Specialty Clinic, Sioux Falls, SD 57105, USA; Barrow Neurological Institute and Ronald A. Matricaria Institute of Molecular Medicine, Phoenix Children's Hospital, Phoenix, AZ 57117, USA.
Quinn SteinBarrow Neurological Institute and Ronald A. Matricaria Institute of Molecular Medicine, Phoenix Children's Hospital, Phoenix, AZ 57117, USA.
Kevin A StraussClinic for Special Children, Franklin & Marshall College, Pennsylvania, PA 17579, USA.
Karlla W BrigattiClinic for Special Children, Franklin & Marshall College, Pennsylvania, PA 17579, USA.
Katherine KeatingDivision of Genetics, Birth Defects & Metabolism, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA.
Barbara K BurtonDivision of Genetics, Birth Defects & Metabolism, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA.
Katherine H KimDivision of Genetics, Birth Defects & Metabolism, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA.
Joel CharrowDivision of Genetics, Birth Defects & Metabolism, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA.
Jennifer NormanIntegris Pediatric Neurology, Oklahoma City, OK 73112, USA.
Audrey Foster-BarberChild Neurology and Palliative Care, Benioff Children's Hospital, San Francisco, CA 94925, USA.
Antonie D KlineThe Harvey Institute for Human Genetics, Greater Baltimore Medical Center, Baltimore, MD 21204, USA.
Amy KimballThe Harvey Institute for Human Genetics, Greater Baltimore Medical Center, Baltimore, MD 21204, USA.
Elaine ZackaiDepartment of Pediatrics, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Margaret HarrDepartment of Pediatrics, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Joyce FoxDivision of Medical Genetics, Cohen Children's Medical Center, New Hyde Park, NY 11040, USA.
Julie McLaughlinDivision of Medical Genetics, Cohen Children's Medical Center, New Hyde Park, NY 11040, USA.
Kristin LindstromDivision of Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, AZ 85006, USA.
Katrina M HaudeUniversity of Rochester Medical Center, Rochester, NY 14642, USA.
Kees van RoozendaalDepartment of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht UMC+, 6202 AZ Maastricht, the Netherlands.
Han BrunnerDepartment of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht UMC+, 6202 AZ Maastricht, the Netherlands.
Wendy K ChungDepartments of Pediatrics & Medicine, Columbia University Medical Center, New York, NY 10032, USA.
R Frank KooyDepartment of Medical Genetics, University of Antwerp and University Hospital Antwerp, 2650 Antwerp, Belgium.
Rolph PfundtDepartment of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
Vera KalscheuerDepartment of Human Genetics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
Sarju G MehtaEast Anglian Regional Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
Nicholas KatsanisCenter for Human Disease Modeling, Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: nicholas.katsanis@duke.edu.
Tjitske KleefstraDepartment of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands. Electronic address: tjitske.kleefstra@radboudumc.nl.
Radboud University Medical Center · NLRadboud University Nijmegen · NLMaastricht University Medical Centre · NLLurie Children's Hospital · USMax Planck Institute for Molecular Genetics · DEAntwerp University Hospital · BEChildren's Hospital of Philadelphia · USCohen Children's Medical Center · USDuke University · USGreater Baltimore Medical Center · USPhoenix Children's Hospital · USUniversity Medical Center Utrecht · NLUniversity of Adelaide · AUUniversity of Antwerp · BEAddenbrooke's Hospital · GBAlberta Children's Hospital · CABarrow Neurological Institute · USCleveland Clinic · USClinic for Special Children · USColumbia University Irving Medical Center · US
Funding
Sporadic Mutations and Autism Spectrum DisordersR01MH101221 · NIMH · UNIVERSITY OF WASHINGTON · PI EICHLER, EVAN · 2013 to 2025
$9.2MInstitutional Training Grant in Pediatric Infectious DiseaseT32HD060558 · NICHD · DUKE UNIVERSITY · PI CUNNINGHAM, COLEEN K. · 2011 to 2015
$1.0MMolecular mechanisms of mitochondrial dysfunction in ATP13A2-associated neurodegeK08NS083739 · NINDS · UNIVERSITY OF ARIZONA · PI KRUER, MICHAEL C · 2013 to 2017
$869kHoward Hughes Medical InstituteNICHD NIH HHS 5T32HD060558-04NICHD NIH HHS T32 HD060558NIMH NIH HHS R01 MH101221NINDS NIH HHS K08 NS083739
Abstract
Intellectual disability (ID) affects approximately 1%-3% of humans with a gender bias toward males. Previous studies have identified mutations in more than 100 genes on the X chromosome in males with ID, but there is less evidence for de novo mutations on the X chromosome causing ID in females. In this study we present 35 unique deleterious de novo mutations in DDX3X identified by whole exome sequencing in 38 females with ID and various other features including hypotonia, movement disorders, behavior problems, corpus callosum hypoplasia, and epilepsy. Based on our findings, mutations in DDX3X are one of the more common causes of ID, accounting for 1%-3% of unexplained ID in females. Although no de novo DDX3X mutations were identified in males, we present three families with segregating missense mutations in DDX3X, suggestive of an X-linked recessive inheritance pattern. In these families, all males with the DDX3X variant had ID, whereas carrier females were unaffected. To explore the pathogenic mechanisms accounting for the differences in disease transmission and phenotype between affected females and affected males with DDX3X missense variants, we used canonical Wnt defects in zebrafish as a surrogate measure of DDX3X function in vivo. We demonstrate a consistent loss-of-function effect of all tested de novo mutations on the Wnt pathway, and we further show a differential effect by gender. The differential activity possibly reflects a dose-dependent effect of DDX3X expression in the context of functional mosaic females versus one-copy males, which reflects the complex biological nature of DDX3X mutations.
Indexed as
PhenotypeSex CharacteristicsAmino Acid SubstitutionAnimalsBase SequenceDEAD-box RNA HelicasesEmbryo, NonmammalianExomeFemaleGene DosageHumansIntellectual DisabilityMaleMolecular Sequence DataMutation, MissenseSequence Analysis, DNADDX3X protein, humanDEAD-box RNA Helicases
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