IQSEC2-related encephalopathy in males and females: a comparative study including 37 novel patients
Mignot, Cyril; McMahon, Aoife C; Bar, Claire; Campeau, Philippe M; Davidson, Claire; Buratti, Julien; Nava, Caroline; Jacquemont, Marie-Line; Tallot, Marilyn; Milh, Mathieu; Edery, Patrick; Marzin, Pauline; Barcia, Giulia; Barnerias, Christine; Besmond, Claude; Bienvenu, Thierry; Bruel, Ange-Line; Brunga, Ledia; Ceulemans, Berten; Coubes, Christine; Cristancho, Ana G; Cunningham, Fiona; Dehouck, Marie-Bertille; Donner, Elizabeth J; Duban-Bedu, Bénédicte; Dubourg, Christèle; Gardella, Elena; Gauthier, Julie; Geneviève, David; Gobin-Limballe, Stéphanie; Goldberg, Ethan M; Hagebeuk, Eveline; Hamdan, Fadi F; Hančárová, Miroslava; Hubert, Laurence; Ioos, Christine; Ichikawa, Shoji; Janssens, Sandra; Journel, Hubert; Kaminska, Anna; Keren, Boris; Koopmans, Marije; Lacoste, Caroline; Laššuthová, Petra; Lederer, Damien; Lehalle, Daphné; Marjanovic, Dragan; Métreau, Julia; Michaud, Jacques L; Miller, Kathryn; Minassian, Berge A; Morales, Joannella; Moutard, Marie-Laure; Munnich, Arnold; Ortiz-Gonzalez, Xilma R; Pinard, Jean-Marc; Prchalová, Darina; Putoux, Audrey; Quelin, Chloé; Rosen, Alyssa R; Roume, Joelle; Rossignol, Elsa; Simon, Marleen E H; Smol, Thomas; Shur, Natasha; Shelihan, Ivan; Štěrbová, Katalin; Vyhnálková, Emílie; Vilain, Catheline; Soblet, Julie; Smits, Guillaume; Yang, Samuel P; van der Smagt, Jasper J; van Hasselt, Peter M; van Kempen, Marjan; Weckhuysen, Sarah; Helbig, Ingo; Villard, Laurent; Héron, Delphine; Koeleman, Bobby; Møller, Rikke S; Lesca, Gaetan; Helbig, Katherine L; Nabbout, Rima; Verbeek, Nienke E; Depienne, Christel
(2019) Genetics in Medicine, volume 21, issue 4, pp. 837 - 849
(Article)
Abstract
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 METHODS: We collected the data of 37 unpublished patients (18 males and 19 females) with IQSEC2 pathogenic variants and 5 individuals with variants of unknown significance
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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.
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Keywords: epilepsy, IQSEC2, isoforms, X-linked inheritance, intellectual disability, Seizures/epidemiology, Humans, Infant, Male, Protein Isoforms/genetics, Brain Diseases/epidemiology, Guanine Nucleotide Exchange Factors/genetics, Sex Characteristics, Intellectual Disability/epidemiology, Brain/growth & development, Phenotype, Pedigree, Female, Mutation, Infant, Newborn, Genetics(clinical), Research Support, Non-U.S. Gov't, Journal Article
ISSN: 1098-3600
Publisher: Lippincott Williams and Wilkins
Note: Funding Information: The authors thank the patients and their families for their participation in this study, Pierre Levy (Hôpital Tenon, Paris) for helpful discussion, and Zdeněk Sedláček (Charles University, Prague) for critical reading of the manuscript. The research generating these results was financially supported by INSERM, ANR (SyndivAutism), APHP (DHOS), the Bio-Psy Labex, Fondation de France, the “Investissements d’avenir” program ANR-10-IAIHU-06 (IHU-A-ICM), a MH CR AZV 15-33041 grant, a 17-29423A grant from the Czech Ministry of Health, and the Wellcome Trust (grant number WT200990/Z/16/Z) and the European Molecular Biology Laboratory. We also thank the Neurology departement of UK Essen (Klinik für Neurologie, Prof. Christoph Kleinschnitz) for supporting Open Access of this article. Publisher Copyright: © 2018, American College of Medical Genetics and Genomics. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
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