Novel familial IQSEC2 pathogenic sequence variant associated with neurodevelopmental disorders and epilepsy


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.

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Data availability

The microarray data obtained in the present study are available in the Array Express database ( in the txt format under the accession number E-MTAB-8147. The NGS data analyzed in this study are available in the Array Express database ( in fastq and bam formats under the accession number E-MTAB-8131. Sanger sequencing data, including the chromatograms of the probands and the parents, are stored in the Figshare online digital repository ( The novel IQSEC2 gene variant NM_001111125.2:c.1813_1814del was submitted to Leiden Open Variation Database v.3.0 (Global Variome shared LOVD) under the accession number #0000629453 ( The variants and phenotypes were submitted to Leiden Open Variation Database v.3.0 (Global Variome shared LOVD). The novel IQSEC2 gene variant NM_001111125.2:c.1813_1814del is available under the accession number #0000629453 ( The BTD gene variant NM_000060.2:c.1330G>C is available under the accession number #0000629454 (


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Core Facility Bioinformatics of CEITEC Masaryk University is gratefully acknowledged for obtaining of the scientific data presented in this paper. Computational resources were provided by the CESNET LM2015042 and the CERIT Scientific Cloud LM2015085, provided under the programme “Projects of Large Research, Development, and Innovations Infrastructures”. The authors are thankful to the family for its participation, and all physicians and medical staff providing the specialized medical examinations supporting and completing the diagnosis of our patients. This work greatly extends the poster presentation by the second author MR on AES 2019 Annual Meeting.


This work was supported by the grant of the Ministry of Health, Czech Republic, Conceptual Development of Research Organization (FNBr, 65269705); by the grant of the Faculty of Science, Masaryk University, Brno, Czech Republic (MUNI/A/1127/2019); and by the grant of the Ministry of Health, Czech Republic, Czech Health Research Council (NU20-07-00145).

Author information




All authors contributed to the study conception and design. MW analyzed and interpreted the NGS data regarding the probands’ phenotypes using relevant literature, bioinformatics databases, and in silico tools. MW was a major contributor in writing the manuscript. MR provided specialized neurological examination and clinical data from the Clinic of Children’s Neurology. JO processed raw NGS data using advanced bioinformatics tools through a unique multistep pipeline. VV, EH, and HP participated in microarray and NGS data analyses and targeted Sanger sequencing analyses. LK performed X chromosome inactivation analysis. MV performed the cytogenetic analysis of karyotype. RG provided specialized genetic counselling for the probands and their family and interpreted the findings in the clinical context. PK contributed towards the interpretation of data and performed general scientific supervision and general critical revision of the manuscript.

Corresponding author

Correspondence to Petr Kuglik.

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The authors declare that they have no conflict of interest.

Ethics approval

All procedures performed involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Approval was obtained from the Ethics Committee of the University Hospital Brno.

Informed Consent

Written institutional informed consent (University Hospital Brno, Czech Republic) was obtained from the parents of the patients before the procedure of genetic analyses. Our case report does not include any personal information leading to the identification of any participants.

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Wayhelova, M., Ryzí, M., Oppelt, J. et al. Novel familial IQSEC2 pathogenic sequence variant associated with neurodevelopmental disorders and epilepsy. Neurogenetics (2020).

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  • Neurodevelopmental disorders
  • Epilepsy
  • Targeted NGS
  • Pathogenic sequence variant
  • IQSEC2 gene