Novel familial IQSEC2 pathogenic sequence variant associated with neurodevelopmental disorders and epilepsy
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ORIGINAL ARTICLE
Novel familial IQSEC2 pathogenic sequence variant associated with neurodevelopmental disorders and epilepsy Marketa Wayhelova 1,2 & Michal Ryzí 3 & Jan Oppelt 4 & Eva Hladilkova 2 & Vladimira Vallova 1,2 & Lenka Krskova 5 & Marcela Vilemova 2 & Hana Polackova 1 & Renata Gaillyova 2 & Petr Kuglik 1,2 Received: 13 January 2020 / Accepted: 11 May 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Pathogenic sequence variants in the IQ motif– and Sec7 domain–containing protein 2 (IQSEC2) gene have been confirmed as causative in the aetiopathogenesis of neurodevelopmental disorders (intellectual disability, autism) and epilepsy. We report on a case of a family with three sons; two of them manifest delayed psychomotor development and epilepsy. Initially proband A was examined using a multistep molecular diagnostics algorithm, including karyotype and array-comparative genomic hybridization analysis, both with negative results. Therefore, probands A and B and their unaffected parents were enrolled for an analysis using targeted “next-generation” sequencing (NGS) with a gene panel ClearSeq Inherited DiseaseXT (Agilent Technologies) and verification analysis by Sanger sequencing. A novel frameshift variant in the X-linked IQSEC2 gene NM_001111125.2:c.1813_1814del, p.(Asp605Profs*3) on protein level, was identified in both affected probands and their asymptomatic mother, having skewed X chromosome inactivation (XCI) (100:0). As the IQSEC2 gene is a known gene escaping from XCI in humans, we expect the existence of mechanisms maintaining the normal or enough level of the IQSEC2 protein in the asymptomatic mother. Further analyses may help to the characterization of the presented novel frameshift variant in the IQSEC2 gene as well as to elucidate the mechanisms leading to the rare asymptomatic phenotypes in females. Keywords Neurodevelopmental disorders . Epilepsy . Targeted NGS . Pathogenic sequence variant . IQSEC2 gene
Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10048-020-00616-3) contains supplementary material, which is available to authorized users. * Petr Kuglik [email protected] Marketa Wayhelova [email protected] 1
Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
2
Department of Medical Genetics, University Hospital Brno, Brno, Czech Republic
3
Clinic of Children’s Neurology, University Hospital Brno, Brno, Czech Republic
4
CEITEC-Central European Institute of Technology, Masaryk University, Brno, Czech Republic
5
Department of Pathology and Molecular Medicine, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czech Republic
The whole-genomic analyses using “next-generation” sequencing (NGS) have significantly increased our understanding of the pathogenesis of neurodevelopmental disorders (NDDs). Recent database outputs point out the causative or candidate impact of approximately 2300 genes in their pa
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