Pantea Cristina-Loredana, Bataneant Mihaela, Zimbru Cristian G, Dragulescu Bogdan, Munteanu Catalin Vasile, Chirita-Emandi Adela
Regional Center of Medical Genetics Timis, Clinical Emergency Hospital for Children "Louis Turcanu", Part of ERN ITHACA, Timisoara, Timis, Romania.
Doctoral School, "Victor Babes" University of Medicine and Pharmacy Timisoara, Timisoara, Romania.
Sci Rep. 2025 May 29;15(1):18830. doi: 10.1038/s41598-025-03492-9.
Inborn errors of immunity (IEI) are monogenic disorders with a wide spectrum of clinical phenotypes including immune dysregulation, autoimmunity, autoinflammation, and malignancy. IEI may have life-threatening consequences, thus precise and timely genetic diagnosis is crucial for improved access to treatment, genetic counselling and prevention. We aimed to investigate the genotypic findings in a cohort of children with IEI from Romania, in order to understand the diagnostic yield of genetic testing, genetic characterization of IEI and impact of genetic diagnosis. Clinical and genetic investigations were performed in 92 children (50% boys) with IEI phenotype, evaluated between 2018 and 2024, in a tertiary reference genetic center in Timisoara, Romania. Sanger sequencing, next generation sequencing panels with genes associated with IEI (1-474 genes), WES and WGS were used. Disease-causing variants for IEI (pathogenic/likely pathogenic) were identified in 37/92 (40.2%) participants, in 25 genes. 14/92 (15.2%) participants had relevant variants of uncertain significance. Median age at genetic testing was 4.38 (IQR 2-12.8) years. 15/37 (40.5%) of patients with Disease-causing variants had a family history of IEI. NGS gene panels were used in 43/92 (46.7%) patients, WES in 29 (31.5%), while WGS in 20 (21.7%). Twelve patients had more than one genetic test. Most frequent genes with Disease-causing variants identified were: JAGN1(5 patients) and AIRE(3). A great variety of genes were identified as causative for IEI. Considering the highly variable and unspecific phenotype, together with no family history in most cases, prioritizing genetic investigations offers the best option for timely diagnosis and treatment.
遗传性免疫缺陷病（IEI）是单基因疾病，具有广泛的临床表型，包括免疫失调、自身免疫、自身炎症和恶性肿瘤。IEI可能会产生危及生命的后果，因此准确及时的基因诊断对于改善治疗途径、遗传咨询和预防至关重要。我们旨在调查一组来自罗马尼亚的患有IEI的儿童的基因型结果，以了解基因检测的诊断率、IEI的基因特征以及基因诊断的影响。2018年至2024年期间，在罗马尼亚蒂米什瓦拉的一家三级参考基因中心，对92名患有IEI表型的儿童（50%为男孩）进行了临床和基因研究。使用了桑格测序、与IEI相关基因的二代测序面板（1 - 474个基因）、全外显子组测序（WES）和全基因组测序（WGS）。在92名参与者中的37名（40.2%）中鉴定出了IEI的致病变体（致病/可能致病），涉及25个基因。14/92（15.2%）的参与者有意义不确定的相关变体。基因检测时的中位年龄为4.38（四分位间距2 - 12.8）岁。15/37（40.5%）的患有致病变体的患者有IEI家族史。43/92（46.7%）的患者使用了NGS基因面板，29名（31.5%）使用了WES，20名（21.7%）使用了WGS。12名患者进行了不止一项基因检测。鉴定出的最常见的具有致病变体的基因是：JAGN1（5例患者）和AIRE（3例）。多种基因被确定为IEI的病因。考虑到表型高度可变且不特异，以及大多数情况下没有家族史，优先进行基因研究为及时诊断和治疗提供了最佳选择。
