IQSEC2-related encephalopathy in males and females: a comparative study including 37 novel patients

Cyril Mignot, Aoife C McMahon, Claire Bar, Philippe M Campeau, Claire Davidson, Julien Buratti, Caroline Nava, Marie-Line Jacquemont, Marilyn Tallot, Mathieu Milh, Patrick Edery, Pauline Marzin, Giulia Barcia, Christine Barnerias, Claude Besmond, Thierry Bienvenu, Ange-Line Bruel, Ledia Brunga, Berten Ceulemans, Christine CoubesAna G Cristancho, Fiona Cunningham, Marie-Bertille Dehouck, Elizabeth J Donner, Bénédicte Duban-Bedu, Christèle Dubourg, Elena Gardella, Julie Gauthier, David Geneviève, Stéphanie Gobin-Limballe, Ethan M Goldberg, Eveline Hagebeuk, Fadi F Hamdan, Miroslava Hančárová, Laurence Hubert, Christine Ioos, Shoji Ichikawa, Sandra Janssens, Hubert Journel, Anna Kaminska, Boris Keren, Marije Koopmans, Caroline Lacoste, Petra Laššuthová, Damien Lederer, Daphné Lehalle, Dragan Marjanovic, Julia Métreau, Jacques L Michaud, Kathryn Miller, Berge A Minassian, Joannella Morales, Marie-Laure Moutard, Arnold Munnich, Xilma R Ortiz-Gonzalez, Jean-Marc Pinard, Darina Prchalová, Audrey Putoux, Chloé Quelin, Alyssa R Rosen, Joelle Roume, Elsa Rossignol, Marleen E H Simon, Thomas Smol, Natasha Shur, Ivan Shelihan, Katalin Štěrbová, Emílie Vyhnálková, Catheline Vilain, Julie Soblet, Guillaume Smits, Samuel P Yang, Jasper J van der Smagt, Peter M van Hasselt, Marjan van Kempen, Sarah Weckhuysen, Ingo Helbig, Laurent Villard, Delphine Héron, Bobby Koeleman, Rikke S Møller, Gaetan Lesca, Katherine L Helbig, Rima Nabbout, Nienke E Verbeek, Christel Depienne

Publikation: Bidrag til tidsskriftArtikelForskningpeer review


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Methods: We collected the data of 37 unpublished patients (18 males and 19 females) with IQSEC2 pathogenic variants and 5 individuals with variants of unknown significance and reviewed published variants.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.

This Article was originally published under Nature Research's License to Publish, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the Article have been modified accordingly.

Sider (fra-til)837-849
Antal sider12
TidsskriftGenetics in Medicine
Udgave nummer4
StatusUdgivet - apr. 2019

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