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 Disease^XT (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.

中文翻译：

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与神经发育障碍和癫痫相关的新型家族性IQSEC2致病性序列变异。

IQ基序和包含Sec7域的蛋白2（IQSEC2）基因中的致病序列变异已被证实是神经发育障碍（智力障碍，自闭症）和癫痫的发病机理中的致病原因。我们报告了一个有三个儿子的家庭的案例；其中两个表现出精神运动发育和癫痫延迟。最初，先证者A使用多步分子诊断算法进行了检查，包括核型和阵列比较基因组杂交分析，均获得阴性结果。因此，先证者A和B及其未受影响的父母参加了使用带有基因组ClearSeq Inherited Disease ^XT的靶向“下一代”测序（NGS）进行分析（Agilent Technologies）和Sanger测序进行的验证分析。X连锁的IQSEC2基因NM_001111125.2：c.1813_1814del，p。（Asp605Profs * 3）在蛋白质水平上发现了一个新的移码变体，在受影响的先证者及其无症状母亲中均具有偏斜的X染色体失活（XCI）（ 100：0）。由于IQSEC2基因是人类XCI逃逸的已知基因，我们期望在无症状的母亲中存在维持IQSEC2蛋白正常或足够水平的机制。进一步的分析可能有助于表征IQSEC2基因中新出现的移码变体，并阐明导致女性罕见的无症状表型的机制。