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
• Epilepsy, IQSEC2 gene, Neurodevelopmental disorders, Pathogenic sequence variant, Targeted NGS,
• MeSH
• Algorithms MeSH
• Gene Deletion MeSH
• Child MeSH
• Epilepsy complications   genetics   MeSH
• Phenotype MeSH
• Genetic Variation * MeSH
• X Chromosome Inactivation MeSH
• Karyotyping MeSH
• Humans MeSH
• Neurodevelopmental Disorders complications   genetics   MeSH
• Frameshift Mutation MeSH
• Child, Preschool MeSH
• Chromosome Banding MeSH
• Oligonucleotide Array Sequence Analysis MeSH
• Comparative Genomic Hybridization * MeSH
• Guanine Nucleotide Exchange Factors genetics   MeSH
• High-Throughput Nucleotide Sequencing MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• IQSEC2 protein, human MeSH Browser
• Guanine Nucleotide Exchange Factors MeSH

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.

• Keywords
• IQSEC2, X-linked inheritance, epilepsy, intellectual disability, isoforms,
• MeSH
• Phenotype MeSH
• Infant MeSH
• Humans MeSH
• Intellectual Disability epidemiology   genetics   physiopathology   MeSH
• Brain growth & development   metabolism   MeSH
• Mutation MeSH
• Brain Diseases epidemiology   genetics   physiopathology   MeSH
• Infant, Newborn MeSH
• Sex Characteristics MeSH
• Protein Isoforms genetics   MeSH
• Pedigree MeSH
• Guanine Nucleotide Exchange Factors genetics   MeSH
• Seizures epidemiology   genetics   physiopathology   MeSH
• Check Tag
• Infant MeSH
• Humans MeSH
• Male MeSH
• Infant, Newborn MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• IQSEC2 protein, human MeSH Browser
• Protein Isoforms MeSH
• Guanine Nucleotide Exchange Factors MeSH

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• Publication type
• Published Erratum MeSH