ArticleGenetics in medicine : official journal of the American College of Medical Genetics2019
IQSEC2-related encephalopathy in males and females: a comparative study including 37 novel patients.
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Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 33 papers.
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33citing papers in PubMed
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33 citing papers in PubMed, 57 citations in OpenAlex.
- 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
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- eIF5A and hypusination-related disorders: literature review and case report of DOHH-related encephalopathy.Journal of neurodevelopmental disorders · 2025Review
- Sex differences in risk factors for Alzheimer dementia encephalopathy patients.Frontiers in dementia · 2025Article
- A Comprehensive Overview of the Current Status and Advancements in Various Treatment Strategies against Epilepsy.ACS pharmacology & translational science · 2024Review
- C-terminal truncations in IQSEC2: implications for synaptic localization, guanine nucleotide exchange factor activity, and neurological manifestations.Journal of human genetics · 2024Article
- Preliminary Study on Clinical Characteristics and Pathogenesis ofPharmacogenomics and personalized medicine · 2024Article
- Ca2+-induced release of IQSEC2/BRAG1 autoinhibition under physiological and pathological conditions.The Journal of cell biology · 2023Article
- A higher dysregulation burden of brain DNA methylation in female patients implicated in the sex bias of Schizophrenia.Molecular psychiatry · 2023Article
- Natural Course ofChildren (Basel, Switzerland) · 2023Article
- Molecular Insights into IQSEC2 Disease.International journal of molecular sciences · 2023Review
- Response to Steroids in IQSEC2-Related Encephalopathy Presenting with Rett-Like Phenotype and Infantile Spasms.Journal of pediatric genetics · 2023Article
- Daily Brief Heat Therapy Reduces Seizures in A350V IQSEC2 Mice and Is Associated with Correction of AMPA Receptor-Mediated Synaptic Dysfunction.International journal of molecular sciences · 2023Article
- A Higher Dysregulation Burden of Brain DNA Methylation in Female Patients Implicated in the Sex Bias of Schizophrenia.Research square · 2023Article
- Systematic analysis and prediction of genes associated with monogenic disorders on human chromosome X.Nature communications · 2022Article
- IQSEC2-related encephalopathy in males due to missense variants in the pleckstrin homology domain.Clinical genetics · 2022Article
- Phenotype and genotype spectrum of variants in guanine nucleotide exchange factor genes in a broad cohort of Iranian patients.Molecular genetics & genomic medicine · 2022Article
- Article
- Phenotypic homogeneity in childhood epilepsies evolves in gene-specific patterns across 3251 patient-years of clinical data.European journal of human genetics : EJHG · 2021Article
- Reduction in seizure burden in a child with a A350V IQSEC2 mutation using heat therapy with a Jacuzzi.Clinical case reports · 2021Article
Corrections and comments
- Erratum issued
Authors and funding
86 authors at 20 institutions in 9 countries.
Cyril MignotINSERM, U 1127, CNRS UMR 7225, Sorbonne Universites, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle epiniere, ICM, Paris, France. cyril.mignot@aphp.fr.
Aoife C McMahonEuropean Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
Claire BarAPHP, Reference Centre for Rare Epilepsies, Necker-Enfants Malades Hospital, Imagine Institute, Paris Descartes University, Paris, France.
Philippe M CampeauDivision of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine and University of Montreal, Montreal, QC, Canada.
Claire DavidsonEuropean Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
Julien BurattiAPHP, Hôpital Pitie-Salpetriere, Departement de Genetique et de Cytogenetique; Centre de Reference Deficience Intellectuelle de Causes Rares; GRC UPMC «Deficience Intellectuelle et Autisme», Paris, France.
Caroline NavaINSERM, U 1127, CNRS UMR 7225, Sorbonne Universites, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle epiniere, ICM, Paris, France.
Marie-Line JacquemontCHU La Reunion-Groupe Hospitalier Sud Reunion, La Reunion, France.
Marilyn TallotCHU La Reunion-Groupe Hospitalier Sud Reunion, La Reunion, France.
Mathieu MilhAPHM, Hôpital d'Enfants de La Timone, Service de Neurologie Pediatrique, centre de reference deficiences intellectuelles de cause rare, Marseille, France.
Patrick EderyService de Genetique, Centre de Reference Anomalies du Developpement, Hospices Civils de Lyon, Bron, France.
Pauline MarzinAPHP, Hôpital Pitie-Salpetriere, Departement de Genetique et de Cytogenetique; Centre de Reference Deficience Intellectuelle de Causes Rares; GRC UPMC «Deficience Intellectuelle et Autisme», Paris, France.
Giulia BarciaINSERM U1163, Imagine Institute, Paris, France.
Christine BarneriasAPHP, Unite fonctionnelle de Neurologie, Necker-Enfants Malades Hospital, Imagine Institute, Paris Descartes University, Paris, France.
Claude BesmondINSERM U1163, Imagine Institute, Paris, France.
Thierry BienvenuAPHP, Laboratoire de Genetique et Biologie Moleculaires, Hôpital Cochin, HUPC, Paris, France.
Ange-Line BruelFHU-TRANSLAD, Universite de Bourgogne/CHU Dijon, Dijon, France.
Ledia BrungaDivision of Neurology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
Berten CeulemansDepartment of Pediatric Neurology, University Hospital and University of Antwerp, Antwerp, Belgium.
Christine CoubesDepartement de Genetique Medicale, Maladies rares et Medecine Personnalisee, CHU de Montpellier, Montpellier, France.
Ana G CristanchoDivision of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Fiona CunninghamEuropean Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
Marie-Bertille DehouckCentre de Genetique Chromosomique, Hôpital St-Vincent-de-Paul, GHICL, Lille, France.
Elizabeth J DonnerDivision of Neurology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
Bénédicte Duban-BeduCentre de Genetique Chromosomique, Hôpital St-Vincent-de-Paul, GHICL, Lille, France.
Christèle DubourgCHU Rennes, Service de Genetique Moleculaire et Genomique, Rennes, France.
Elena GardellaDanish Epilepsy Centre Filadelfia, Dianalund, Denmark.
Julie GauthierDivision of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine and University of Montreal, Montreal, QC, Canada.
David GenevièveDepartement de Genetique Medicale, Maladies rares et Medecine Personnalisee, CHU de Montpellier, Montpellier, France.
Stéphanie Gobin-LimballeAPHP, Service de genetique medicale, Necker-Enfants Malades Hospital, Imagine Institute, Paris Descartes University, Paris, France.
Ethan M GoldbergDivision of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Eveline HagebeukStichting Epilepsie Instellingen Nederland, SEIN, Zwolle, The Netherlands.
Fadi F HamdanDivision of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine and University of Montreal, Montreal, QC, Canada.
Miroslava HančárováDepartment of Biology and Medical Genetics, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
Laurence HubertINSERM U1163, Imagine Institute, Paris, France.
Christine IoosAPHP, University Hospital of Paris ïle-de-France ouest, Raymond Poincare Hospital, Garches, France.
Shoji IchikawaDepartment of Clinical Diagnostics, Ambry Genetics, Aliso Viejo, CA, USA.
Sandra JanssensCentre for Medical Genetics Ghent, Ghent University Hospital, C. Heymanslaan 10, Ghent, Belgium.
Hubert JournelService de Genetique Medicale, Hôpital Chubert, Vannes, France.
Anna KaminskaAPHP, Department of Clinical Neurophysiology, Necker-Enfants Malades Hospital, Paris, France.
Boris KerenAPHP, Hôpital Pitie-Salpetriere, Departement de Genetique et de Cytogenetique; Centre de Reference Deficience Intellectuelle de Causes Rares; GRC UPMC «Deficience Intellectuelle et Autisme», Paris, France.
Marije KoopmansDepartment of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Caroline LacosteDepartement de Genetique Medicale, APHM, Hopital d'Enfants de La Timone, Marseille, France.
Petra LaššuthováChild Neurology Department, 2nd Faculty of Medicine, Charles University and Motol Hospital, Prague, Czech Republic.
Damien LedererCentre de Genetique Humaine, Institut de Pathologie et de Genetique, Gosselies, Belgium.
Daphné LehalleFHU-TRANSLAD, Universite de Bourgogne/CHU Dijon, Dijon, France.
Dragan MarjanovicDanish Epilepsy Centre Filadelfia, Dianalund, Denmark.
Julia MétreauAPHP, Service de neurologie pediatrique, Hôpital Universitaire Bicetre, Le Kremlin-Bicetre, France.
Jacques L MichaudDivision of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine and University of Montreal, Montreal, QC, Canada.
Kathryn MillerDepartment of Pediatrics, Albany Medical Center, Albany, NY, USA.
Berge A MinassianDivision of Neurology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
Joannella MoralesEuropean Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
Marie-Laure MoutardAPHP, Hôpital Trousseau, service de neuropediatrie, Paris, France.
Arnold MunnichINSERM U1163, Imagine Institute, Paris, France.
Xilma R Ortiz-GonzalezDivision of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Jean-Marc PinardDivision of Neuropediatrics, CHU Raymond Poincare (APHP), Garches, France.
Darina PrchalováDepartment of Biology and Medical Genetics, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
Audrey PutouxService de Genetique, Centre de Reference Anomalies du Developpement, Hospices Civils de Lyon, Bron, France.
Chloé QuelinService de Genetique Medicale, CLAD Ouest CHU Hôpital Sud, Rennes, France.
Alyssa R RosenDivision of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Joelle RoumeUnite de Genetique Medicale, Centre de Reference des Maladies rares du Developpement (AnD DI Rares), CHI Poissy-St Germain en Laye, Poissy, France.
Elsa RossignolDepartments of Pediatrics and Neurosciences, CHU Sainte-Justine and University of Montreal, Montreal, Canada.
Marleen E H SimonDepartment of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Thomas SmolInstitut de Genetique Medicale, CHRU Lille, Universite de Lille, Lille, France.
Natasha ShurDepartment of Pediatrics, Albany Medical Center, Albany, NY, USA.
Ivan ShelihanDivision of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine and University of Montreal, Montreal, QC, Canada.
Katalin ŠtěrbováChild Neurology Department, 2nd Faculty of Medicine, Charles University and Motol Hospital, Prague, Czech Republic.
Emílie VyhnálkováDepartment of Biology and Medical Genetics, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
Catheline VilainDepartment of Genetics, Hôpital Universitaire des Enfants Reine Fabiola, ULB Center of Human Genetics, Universite Libre de Bruxelles, Brussels, Belgium.
Julie SobletDepartment of Genetics, Hôpital Universitaire des Enfants Reine Fabiola, ULB Center of Human Genetics, Universite Libre de Bruxelles, Brussels, Belgium.
Guillaume SmitsDepartment of Genetics, Hôpital Universitaire des Enfants Reine Fabiola, ULB Center of Human Genetics, Universite Libre de Bruxelles, Brussels, Belgium.
Samuel P YangClinical Genomics & Predictive Medicine, Providence Medical Group, Dayton, WA, USA.
Jasper J van der SmagtDepartment of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Peter M van HasseltDepartment of Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Center, Utrecht, The Netherlands.
Marjan van KempenDepartment of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Sarah WeckhuysenNeurogenetics Group, Center of Molecular Neurology, VIB, Antwerp, Belgium.
Ingo HelbigDivision of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Laurent VillardAix Marseille University, INSERM, MMG, UMR-S 1251, Faculte de medecine, Marseille, France.
Delphine HéronAPHP, Hôpital Pitie-Salpetriere, Departement de Genetique et de Cytogenetique; Centre de Reference Deficience Intellectuelle de Causes Rares; GRC UPMC «Deficience Intellectuelle et Autisme», Paris, France.
Bobby KoelemanDepartment of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Rikke S MøllerCHU Rennes, Service de Genetique Moleculaire et Genomique, Rennes, France.
Gaetan LescaService de Genetique, Centre de Reference Anomalies du Developpement, Hospices Civils de Lyon, Bron, France.
Katherine L HelbigDivision of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Rima NabboutAPHP, Reference Centre for Rare Epilepsies, Necker-Enfants Malades Hospital, Imagine Institute, Paris Descartes University, Paris, France.
Nienke E VerbeekDepartment of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Christel DepienneINSERM, U 1127, CNRS UMR 7225, Sorbonne Universites, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle epiniere, ICM, Paris, France. christel.depienne@uni-due.de.
University Medical Center Utrecht · NLCentre Hospitalier Universitaire Sainte-Justine · CAChildren's Hospital of Philadelphia · USCentre d'Épidémiologie sur les Causes Médicales de Décès · FRCharles University · CZAssistance Publique – Hôpitaux de Paris · FREuropean Bioinformatics Institute · GBDélégation Paris 5 · FRInserm · FRAlbany Medical Center Hospital · USCentre Hospitalier Universitaire de La Réunion · FRCentre Hospitalier Universitaire de Rennes · FRCentre National de la Recherche Scientifique · FRFiladelfia · DKHôpital d'Enfants · FRHôpital Raymond-Poincaré · FRInstitut des Maladies Génétiques Imagine · FRUniversity of Toronto · CAAmbry Genetics (United States) · USAntwerp University Hospital · BE
Funding
The Intellectual and Developmental Disabilities Research Center at CHOP/PennU54HD086984 · NICHD · CHILDREN'S HOSP OF PHILADELPHIA · PI SCHULTZ, ROBERT THOMAS · 2016 to 2020
$6.3MNICHD NIH HHS U54 HD086984Wellcome TrustWellcome Trust WT200990/Z/16/Z
Abstract
purposeVariants in IQSEC2, escaping X inactivation, cause X-linked intellectual disability with frequent epilepsy in males and females. We aimed to investigate sex-specific differences.
methodsWe collected the data of 37 unpublished patients (18 males and 19 females) with IQSEC2 pathogenic variants and 5 individuals with variants of unknown significance and reviewed published variants. We compared variant types and phenotypes in males and females and performed an analysis of IQSEC2 isoforms.
resultsIQSEC2 pathogenic variants mainly led to premature truncation and were scattered throughout the longest brain-specific isoform, encoding the synaptic IQSEC2/BRAG1 protein. Variants occurred de novo in females but were either de novo (2/3) or inherited (1/3) in males, with missense variants being predominantly inherited. Developmental delay and intellectual disability were overall more severe in males than in females. Likewise, seizures were more frequently observed and intractable, and started earlier in males than in females. No correlation was observed between the age at seizure onset and severity of intellectual disability or resistance to antiepileptic treatments.
conclusionThis study provides a comprehensive overview of IQSEC2-related encephalopathy in males and females, and suggests that an accurate dosage of IQSEC2 at the synapse is crucial during normal brain development.
Indexed as
BrainBrain DiseasesFemaleGuanine Nucleotide Exchange FactorsHumansInfantInfant, NewbornIntellectual DisabilityMaleMutationPedigreePhenotypeProtein IsoformsSeizuresSex CharacteristicsGuanine Nucleotide Exchange FactorsIQSEC2 protein, humanProtein Isoformsepilepsyintellectual disabilityIQSEC2isoformsX-linked inheritance
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