Scott Ori, Dadi Harjit, Vong Linda, Pasternak Yehonatan, Garkaby Jenny, Willett Pachul Jessica, Mandola Amarilla B, Brager Rae, Hostoffer Robert, Nahum Amit, Roifman Chaim M
Division of Immunology and Allergy, Department of Paediatrics, Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.
The Canadian Centre for Primary Immunodeficiency and The Jeffrey Modell Research Laboratory for the diagnosis of Primary Immunodeficiency, The Hospital for Sick Children, Toronto, Ontario, Canada.
Pediatr Allergy Immunol. 2022 Jan;33(1):e13694. doi: 10.1111/pai.13694. Epub 2021 Nov 18.
STAT1 gain-of-function (GOF) is an immune dysregulatory disorder with poorly studied genotype-phenotype correlation, impeding prognostication and early intervention. Given previous mechanistic studies, as well as anecdotal clinical reports, we sought to systematically determine whether DNA-binding domain (DBD) mutations in STAT1 result in a different phenotype than mutations in other gene domains.
Negative prognostic features previously identified by the International STAT1 GOF Study Group (invasive infections, intracranial aneurysms, and malignancy), as well as other clinical features and mortality, were compared within a cohort of 30 patients with STAT1 GOF diagnosed at our center, consisting of 9 patients with DBD mutations and 21 patients with non-DBD mutations. We subsequently re-analyzed mortality data from a large, previously-published 274-patient cohort by the International STAT1 GOF Study Group.
While no differences were noted with respect to malignancy or symptomatic aneurysms, invasive /opportunistic infections were substantially more common among DBD patients, as were sinopulmonary infections, bronchiectasis, enteropathy, endocrinopathies, lymphoproliferative manifestations, and recurrent fevers/HLH. DBD patients also had a lower probability of survival and younger age of mortality compared with non-DBD patients. Our re-evaluation of the published data from the International STAT1 GOF Study Group revealed a similar finding of earlier mortality among patients harboring DBD mutations.
We report that STAT1 GOF patients with DBD mutations may be regarded as a unique subgroup, impacted more by early-onset profound combined immunodeficiency and with earlier mortality. These findings may impact clinical decision making with respect to early intervention, and in particular hematopoietic stem cell transplant considerations, in such patients.
信号转导和转录激活因子1（STAT1）功能获得性突变（GOF）是一种免疫调节紊乱疾病，其基因型与表型的相关性研究较少，这阻碍了预后评估和早期干预。鉴于先前的机制研究以及临床病例报告，我们试图系统地确定STAT1的DNA结合域（DBD）突变是否会导致与其他基因域突变不同的表型。
在我们中心确诊的30例STAT1 GOF患者队列中，比较了国际STAT1 GOF研究组先前确定的不良预后特征（侵袭性感染、颅内动脉瘤和恶性肿瘤）以及其他临床特征和死亡率，该队列包括9例DBD突变患者和21例非DBD突变患者。随后，我们重新分析了国际STAT1 GOF研究组先前发表的一个包含274例患者的大型队列的死亡率数据。
虽然在恶性肿瘤或有症状的动脉瘤方面未发现差异，但侵袭性/机会性感染在DBD患者中更为常见，鼻窦肺部感染、支气管扩张、肠病、内分泌病、淋巴增殖性表现以及反复发热/噬血细胞性淋巴组织细胞增生症（HLH）也是如此。与非DBD患者相比，DBD患者的生存概率更低，死亡年龄更小。我们对国际STAT1 GOF研究组发表数据的重新评估显示，携带DBD突变的患者死亡率更早的结果相似。
我们报告，具有DBD突变的STAT1 GOF患者可能被视为一个独特的亚组，受早发性严重联合免疫缺陷的影响更大，且死亡率更早。这些发现可能会影响此类患者早期干预的临床决策，特别是造血干细胞移植的考虑。
