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

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Date: September 14, 2018
Authors:
Ana G. Cristancho, Ange-Line Bruel, Aoife C. McMahon, Berten Ceulemans, Bénédicte Duban-Bedu, Caroline Nava, Christine Barnerias, Christine Coubes, Christine Ioos, Christèle Dubourg, Claire Bar, Claire Davidson, Claude Besmond, Cyril Mignot, David Geneviève, Elena Gardella, Elizabeth J. Donner, Ethan M. Goldberg, Eveline Hagebeuk, Fadi F. Hamdan, Fiona Cunningham, Giulia Barcia, Julie Gauthier, Julien Buratti, Laurence Hubert, Ledia Brunga, Marie-Bertille Dehouck, Marie-Line Jacquemont, Marilyn Tallot, Mathieu Milh, Miroslava Hančárová, Patrick Edery, Pauline Marzin, Philippe M Campeau, Shoji Ichikawa, Stéphanie Gobin-Limballe, Thierry Bienvenu
Journal: Genetics in Medicine
Topics:
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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We collected the data of 37 unpublished patients (18 males and 19 females) with IQSEC2 pathogenic variants and 5 individuals with variants of unknown significance and reviewed published variants.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.