PURPOSE: Variants in IQSEC2, escaping X inactivation, cause X-linked intellectual disability with frequent epilepsy in males and females. We aimed to investigate sex-specific differences. METHODS: We collected the data of 37 unpublished patients (18 males and 19 females) with IQSEC2 pathogenic variants and 5 individuals with variants of unknown significance and reviewed published variants.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. RESULTS: IQSEC2 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. CONCLUSION: This 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.

Aix Marseille University INSERM MMG UMR S 1251 Faculte de medecine Marseille France

APHM Hôpital d'Enfants de La Timone Service de Neurologie Pediatrique centre de reference deficiences intellectuelles de cause rare Marseille France

APHP Department of Clinical Neurophysiology Necker Enfants Malades Hospital Paris France

APHP 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

APHP Hôpital Trousseau service de neuropediatrie Paris France

APHP Laboratoire de Genetique et Biologie Moleculaires Hôpital Cochin HUPC Paris France

APHP Reference Centre for Rare Epilepsies Necker Enfants Malades Hospital Imagine Institute Paris Descartes University Paris France

APHP Service de genetique medicale Necker Enfants Malades Hospital Imagine Institute Paris Descartes University Paris France

APHP Service de neurologie pediatrique Hôpital Universitaire Bicetre Le Kremlin Bicetre France

APHP Unite fonctionnelle de Neurologie Necker Enfants Malades Hospital Imagine Institute Paris Descartes University Paris France

APHP University Hospital of Paris ïle de France ouest Raymond Poincare Hospital Garches France

Centre de Genetique Chromosomique Hôpital St Vincent de Paul GHICL Lille France

Centre de Genetique Humaine Institut de Pathologie et de Genetique Gosselies Belgium

Centre for Medical Genetics Ghent Ghent University Hospital C Heymanslaan 10 Ghent Belgium

Child Neurology Department 2nd Faculty of Medicine Charles University and Motol Hospital Prague Czech Republic

CHU La Reunion Groupe Hospitalier Sud Reunion La Reunion France

CHU Rennes Service de Genetique Moleculaire et Genomique Rennes France

Claude Bernard Lyon 1 University Lyon France

Clinical Genomics and Predictive Medicine Providence Medical Group Dayton WA USA

Danish Epilepsy Centre Filadelfia Dianalund Denmark

Departement de Genetique Medicale APHM Hopital d'Enfants de La Timone Marseille France

Departement de Genetique Medicale Maladies rares et Medecine Personnalisee CHU de Montpellier Montpellier France

Department of Biology and Medical Genetics Charles University 2nd Faculty of Medicine and University Hospital Motol Prague Czech Republic

Department of Clinical Diagnostics Ambry Genetics Aliso Viejo CA USA

Department of Genetics Hôpital Erasme ULB Center of Human Genetics Universite Libre de Bruxelles Brussels Belgium

Department of Genetics Hôpital Universitaire des Enfants Reine Fabiola ULB Center of Human Genetics Universite Libre de Bruxelles Brussels Belgium

Department of Genetics University Medical Center Utrecht Utrecht The Netherlands

Department of Metabolic Diseases Wilhelmina Children's Hospital University Medical Center Utrecht The Netherlands

Department of Pediatric Neurology University Hospital and University of Antwerp Antwerp Belgium

Department of Pediatrics Albany Medical Center Albany NY USA

Departments of Pediatrics and Neurosciences CHU Sainte Justine and University of Montreal Montreal Canada

Division of Medical Genetics Department of Pediatrics CHU Sainte Justine and University of Montreal Montreal QC Canada

Division of Neurology Children's Hospital of Philadelphia Philadelphia PA USA

Division of Neurology Department of Paediatrics The Hospital for Sick Children University of Toronto Toronto ON Canada

Division of Neuropediatrics CHU Raymond Poincare Garches France

European Molecular Biology Laboratory European Bioinformatics Institute Wellcome Genome Campus Hinxton Cambridge UK

FHU TRANSLAD Universite de Bourgogne CHU Dijon Dijon France

IGBMC CNRS UMR 7104 INSERM U964 Universite de Strasbourg Illkirch France

INSERM 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

INSERM U1028 CNRS UMR5292 Centre de Recherche en Neurosciences de Lyon GENDEV Team Universite Claude Bernard Lyon 1 Bron France

INSERM U1163 Imagine Institute Paris France

INSERM U1183 Montpellier France

INSERM UMR 1231 GAD team Genetics of Developmental disorders Universite de Bourgogne Franche Comte Dijon France

Institut de Genetique Medicale CHRU Lille Universite de Lille Lille France

Institute for Regional Health Services University of Southern Denmark Odense Denmark

Institute of Human Genetics University Hospital Essen University of Duisburg Essen Essen Germany

Interuniversity Institute of Bioinformatics in Brussels Universite Libre de Bruxelles Brussels Belgium

Neurogenetics Group Center of Molecular Neurology VIB Antwerp Belgium

Neurology Department University Hospital Antwerp Antwerp Belgium

Paris Descartes University Paris France

Service de Genetique Centre de Reference Anomalies du Developpement Hospices Civils de Lyon Bron France

Service de Genetique Medicale CLAD Ouest CHU Hôpital Sud Rennes France

Service de Genetique Medicale Hôpital Chubert Vannes France

Sorbonne Universite GRC n°19 pathologies Congenitales du Cervelet LeucoDystrophies APHP Hôpital Armand Trousseau Paris France

Stichting Epilepsie Instellingen Nederland SEIN Zwolle The Netherlands

Unite de Genetique Medicale Centre de Reference des Maladies rares du Developpement CHI Poissy St Germain en Laye Poissy France

Unite fonctionnelle de genetique clinique Centre Hospitalier Intercommunal de Creteil Creteil France

Universite Paris Descartes Paris Institut de Psychiatrie et de Neurosciences de Paris Inserm U894 Paris France

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Genet Med. 2019 Aug;21(8):1897-1898. doi: 10.1038/s41436-018-0327-7. PubMed

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