Dataset Information

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

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 METHODS:We collected the data of 37 unpublished patients (18 males and 19 females) with IQSEC2 pathogenic variants and 5 individuals with variants of unknown significance and reviewed published variants.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

SUBMITTER: Mignot C

PROVIDER: S-EPMC6752297 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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

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

Genetics in medicine : official journal of the American College of Medical Genetics 20180912 4

<h4>Purpose</h4>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.<h4>Methods</h4>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 IQS ...[more]

PMID: 30206421

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Project description:The isoleucine-glutamine (IQ) motif and Sec7 domain-containing protein 2 (IQSEC2) gene, located at Xp11. 2, are associated with nervous system diseases, such as epilepsy, autism, and intellectual disabilities. Gender-related differences in the severity of phenotype severity have been described previously. Here, we report the details of seven male children with IQSEC2 mutations from different families. During this investigation, we explored the relationship between the genotype and phenotype of IQSEC2 mutations; to do so, we recruited seven children with pathogenic/likely pathogenic IQSEC2 mutations who were diagnosed with global developmental delay and/or epilepsy. Their clinical features were assessed, and Trio-based whole-exome sequencing (trio WES) was conducted in seven pedigrees. A variety of algorithms and computational tools were used to calculate the pathogenicity, protein stability, conservation, side chain properties, and protein-protein interactions of mutated proteins. The seven patients ranged in age from 18 months to 5 years. Among them, six children were found to have both developmental delay and epilepsy, and one child only exhibited developmental delay. Four novel mutations (c.316C > T, c.443_4 44dup, c.3235T > C, and c.1417G > T) were newly reported. Two patients did not have truncated aberrant proteins caused by missense mutations. Still, they did have severe phenotypes, such as early-onset epilepsy in infancy, because the mutations were located in domains like the pleckstrin homology and IQ calmodulin-binding motif domains. The bioinformatics analysis also proved that missense mutations may be located in the functional region, which affects protein stability and is harmful. In summary, severe phenotypes, such as early-onset epilepsy in infancy, occur in male patients with a missense mutation in specific domains (e.g., pleckstrin homology and IQ calmodulin-binding motif domains). Some female individuals with IQSEC2 mutations may be asymptomatic because of the skewed inactivation of the X chromosome.

Dataset Information

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

Publications

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

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