Interferon-stimulated gene 15 (ISG15) was the first ubiquitin-like modifier protein identified that acts by protein conjugation (ISGylation) and is thought to modulate IFN-induced inflammation. Here, we report a new patient from a non-consanguineous Argentinian family, who was followed for recurrent ulcerative skin lesions, cerebral calcifications and lung disease. Whole Exome Sequencing (WES) revealed two novel compound heterozygous variants (c.285del and c.299_312del, NM_005101.4 GRCh37(hg19), both classified as pathogenic according to ACMG criteria) in the ISG15 gene, resulting in a complete deficiency due to disruption of the second ubiquitin domain of the corresponding protein. The clinical phenotype of this patient is unique given the presence of recurrent pulmonary manifestations and the absence of mycobacterial infections, thus resulting in a phenotype distinct from that previously described in patients with biallelic loss-of-function (LOF) ISG15 variants. This case highlights the role of ISG15 as an immunomodulating factor whose LOF variants result in heterogeneous clinical presentations.

中文翻译：

---

一例常染色体隐性ISG15缺乏症患者的炎症性皮肤病变和肺部表现。

干扰素刺激基因15（ISG15）是第一个被识别为通过蛋白结合（ISGylation）起作用的泛素样修饰蛋白，被认为可调节IFN诱导的炎症。在这里，我们报告了一位来自阿根廷非血缘家庭的新患者，该患者因复发性溃疡性皮肤病变，脑钙化和肺部疾病而接受随访。全外显子组测序（WES）在ISG15基因中发现了两个新的复合杂合变异体（c.285del和c.299_312del，NM_005101.4 GRCh37（hg19），根据ACMG标准均被归类为致病性），导致完全缺失破坏相应蛋白质的第二泛素结构域。鉴于存在反复出现的肺部表现和不存在分枝杆菌感染的情况，该患者的临床表型是独特的，因此产生的表型不同于先前在双等位基因功能丧失（LOF）ISG15变异患者中描述的表型。该病例突出了ISG15作为免疫调节因子的作用，其LOF变异导致异质临床表现。