PURPOSE Haploinsufficiency of PSMD12 has been reported in individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), facial dysmorphism, and congenital malformations, defined as Stankiewicz-Isidor syndrome (STISS). Investigations showed that pathogenic variants in PSMD12 perturb intracellular protein homeostasis. Our objective was to further explore the clinical and molecular phenotypic spectrum of STISS. METHODS We report 24 additional unrelated patients with STISS with various truncating single nucleotide variants or copy-number variant deletions involving PSMD12. We explore disease etiology by assessing patient cells and CRISPR/Cas9-engineered cell clones for various cellular pathways and inflammatory status. RESULTS The expressivity of most clinical features in STISS is highly variable. In addition to previously reported DD/ID, speech delay, cardiac and renal anomalies, we also confirmed preaxial hand abnormalities as a feature of this syndrome. Of note, 2 patients also showed chilblains resembling signs observed in interferonopathy. Remarkably, our data show that STISS patient cells exhibit a profound remodeling of the mTORC1 and mitophagy pathways with an induction of type I interferon-stimulated genes. CONCLUSION We refine the phenotype of STISS and show that it can be clinically recognizable and biochemically diagnosed by a type I interferon gene signature.

中文翻译：

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Stankiewicz-Isidor 综合征：扩大临床和分子表型。

目的 PSMD12 单倍体不足已在具有神经发育表型的个体中报告，包括发育迟缓/智力残疾 (DD/ID)、面部畸形和先天性畸形，定义为 Stankiewicz-Isidor 综合征 (STISS)。研究表明，PSMD12 中的致病变异会扰乱细胞内蛋白质稳态。我们的目标是进一步探索 STISS 的临床和分子表型谱。方法 我们报告了另外 24 名无关的 STISS 患者，这些患者有各种截短的单核苷酸变异或涉及 PSMD12 的拷贝数变异缺失。我们通过评估患者细胞和 CRISPR/Cas9 工程细胞克隆的各种细胞途径和炎症状态来探索疾病病因。结果 STISS 中大多数临床特征的表现是高度可变的。除了先前报道的 DD/ID、言语延迟、心脏和肾脏异常外，我们还证实了轴前手异常是该综合征的一个特征。值得注意的是，2 名患者还表现出类似于在干扰素病中观察到的冻疮症状。值得注意的是，我们的数据显示 STISS 患者细胞表现出 mTORC1 和线粒体自噬途径的深刻重塑，并诱导 I 型干扰素刺激的基因。结论 我们改进了 STISS 的表型，并表明它可以通过 I 型干扰素基因特征进行临床识别和生化诊断。我们的数据表明，STISS 患者细胞表现出 mTORC1 和线粒体自噬途径的深刻重塑，并诱导 I 型干扰素刺激基因。结论 我们改进了 STISS 的表型，并表明它可以通过 I 型干扰素基因特征进行临床识别和生化诊断。我们的数据表明，STISS 患者细胞表现出 mTORC1 和线粒体自噬途径的深刻重塑，并诱导 I 型干扰素刺激基因。结论 我们改进了 STISS 的表型，并表明它可以通过 I 型干扰素基因特征进行临床识别和生化诊断。