Mutations in adaptor protein complex‐4 (AP‐4) genes have first been identified in 2009, causing a phenotype termed as AP‐4 deficiency syndrome. Since then several patients with overlapping phenotypes, comprised of intellectual disability (ID) and spastic tetraplegia have been reported. To delineate the genotype‐phenotype correlation of the AP‐4 deficiency syndrome, we add the data from 30 affected individuals from 12 out of 640 Iranian families with ID in whom we detected disease‐causing variants in AP‐4 complex subunits, using next‐generation sequencing. Furthermore, by comparing genotype‐phenotype findings of those affected individuals with previously reported patients, we further refine the genotype‐phenotype correlation in this syndrome. The most frequent reported clinical findings in the 101 cases consist of ID and/or global developmental delay (97%), speech disorders (92.1%), inability to walk (90.1%), spasticity (77.2%), and microcephaly (75.2%). Spastic tetraplegia has been reported in 72.3% of the investigated patients. The major brain imaging findings are abnormal corpus callosum morphology (63.4%) followed by ventriculomegaly (44.5%). Our result might suggest the AP‐4 deficiency syndrome as a major differential diagnostic for unknown hereditary neurodegenerative disorders.

中文翻译：

---

AP-4缺乏综合征的综合基因型-表型相关性；添加来自大量伊朗患者的数据。

2009 年首次发现了接头蛋白复合物 4 (AP-4) 基因的突变，导致了一种称为 AP-4 缺陷综合征的表型。从那时起，已经报道了一些具有重叠表型的患者，包括智力障碍 (ID) 和痉挛性四肢瘫痪。为了描绘 AP-4 缺乏综合征的基因型-表型相关性，我们添加了来自 640 个伊朗 ID 家庭中的 12 个受影响个体的数据，我们在这些家庭中检测到了 AP-4 复杂亚基中的致病变异，使用 next-代测序。此外，通过将受影响个体的基因型 - 表型结果与先前报告的患者进行比较，我们进一步完善了该综合征中的基因型 - 表型相关性。101 例中最常见的临床发现包括 ID 和/或全面发育迟缓 (97%)、言语障碍 (92.1%)、无法行走 (90.1%)、痉挛 (77.2%) 和小头畸形 (75.2%) ）。72.3% 的受调查患者报告了痉挛性四肢瘫痪。主要的脑成像结果是胼胝体形态异常（63.4%），其次是脑室扩大（44.5%）。我们的结果可能表明 AP-4 缺乏综合征是未知遗传性神经退行性疾病的主要鉴别诊断。