IQSEC2 mutations are associated with IQSEC2‐related intellectual disability (ID). Phenotypic spectrum has been better defined in the last few years by the increasing number of reported cases although the genotype–phenotype relationship for IQSEC2 remains overall complex. As for IQSEC2‐related ID a wide phenotypic diversity has been described in Rett syndrome (RTT). Several patients harboring IQSEC2 mutations present with clinical symptoms similar to RTT and some cases meet most of the criteria for classic RTT. With the aim of establishing a genotype–phenotype correlation, we collected data of 16 patients harboring IQSEC2 point mutations (15 of them previously unreported) and of five novel patients carrying CNVs encompassing IQSEC2. Most of our patients surprisingly shared a moderate‐to‐mild phenotype. The similarities in the clinical course between our mild cases and patients with milder forms of atypical RTT reinforce the hypothesis that also IQSEC2 mutated patients may lay under the wide clinical spectrum of RTT and thus IQSEC2 should be considered in the differential diagnosis. Our data confirm that position, type of variant and gender are crucial for IQSEC2‐associated phenotype delineation.

中文翻译：

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IQSEC2 障碍：新的疾病实体还是 Rett 谱连续体？

IQSEC2突变与IQSEC2相关的智力障碍 (ID) 相关。尽管IQSEC2的基因型-表型关系总体上仍然复杂，但在过去几年中，随着报告病例数量的增加，表型谱得到了更好的定义。至于IQSEC2相关 ID，在雷特综合征 (RTT) 中描述了广泛的表型多样性。一些携带IQSEC2突变的患者表现出类似于 RTT 的临床症状，有些病例符合经典 RTT 的大部分标准。为了建立基因型-表型相关性，我们收集了 16 名携带IQSEC2 的患者的数据点突变（其中 15 个以前未报告）和 5 名携带包含IQSEC2 的CNV 的新患者。我们的大多数患者令人惊讶地具有中度至轻度表型。我们的轻度病例和非典型 RTT 较轻的患者在临床过程中的相似性加强了IQSEC2突变患者也可能属于 RTT 的广泛临床谱的假设，因此在鉴别诊断中应考虑IQSEC2。我们的数据证实，位置、变异类型和性别对于IQSEC2相关表型描绘至关重要。