IFIH1 gain‐of‐function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi–Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate.

中文翻译：

---

与 IFIH1 功能获得相关的遗传和表型谱。

据报道，IFIH1 功能获得是 I 型干扰素病的原因，包括一系列自身炎症表型，包括 Aicardi-Goutières 综合征和 Singleton Merten 综合征。通过欧洲和北美的合作确定患者，我们开始描述IFIH1中具有致病性杂合突变的一组个体的分子、临床和干扰素状态。我们确定了来自 51 个家庭的 74 个人，在IFIH1中分离出总共 27 个可能的致病突变. 10 名成年个体（占所有突变携带者的 13.5%）在临床上无症状（其中 7 人年龄超过 50 岁）。所有突变都与增强的 I 型干扰素信号传导相关，包括根据多重计算机致病性程序预测为良性的六种变体 (22%)。鉴定出的突变簇靠近蛋白质的 ATP 结合区域。这些数据证实了可变表达和非外显率是IFIH1基因型的重要特征，与增强的 I 型干扰素信号传导的一致关联，以及涉及 RNA 结合亲和力增加或 ATP 水解效率和细丝分解率降低的常见突变机制。