Krasnanska Gabriela, Blandova Gabriela, Baldovic Marian, Andrejkova Maria, Konecny Michal
Department of Biology, Institute of Biology and Biotechnology, Faculty of Natural Sciences, University of St. Cyril and Methodius, Trnava, SVK.
Laboratory of Genomic Medicine, GHC GENETICS SK, Comenius University Science Park, Bratislava, SVK.
Cureus. 2024 Dec 17;16(12):e75872. doi: 10.7759/cureus.75872. eCollection 2024 Dec.
X-linked severe combined immunodeficiency disease (X-SCID) is a form of inborn errors of immunity (IEI) associated with causal DNA variants of the gene. Patients with X-SCID are characterized by a combination of cellular and humoral immunodeficiencies associated with increased susceptibility to infections. The presented cases constituted two unrelated male patients from the Slovak population. Proband A was primarily hospitalized at the age of three months because of recurrent fever, vomiting, and lethargy, and the atypical immunophenotype was determined to be T-B-NK-. For proband B, the first hospitalization occurred at the age of eight months because of generalized impetiginized dermatitis. Whole exome sequencing (WES) was performed via a comprehensive approach in patients with undefined IEI, and causal DNA variants were confirmed by Sanger sequencing. WES analysis in probands identified the currently undescribed hemizygous variants p.Asn84Thr and p.Val213Ala in the gene. Segregation analysis of p.Asn84Thr indicated a de novo origin, and p.Val213Ala was detected only in the asymptomatic proband's mother. We comprehensively reconsidered and scored both variants based on biological and clinical aspects. Finally, taking all the information into account, we classified p.Asn84Thr as likely pathogenic and p.Val213Ala as likely pathogenic with mild penetrance based on the fulfilled ACMG (American College of Medical Genetics and Genomics) criteria for computational predictions, clinical correlations, localization at functional site, and de novo status. With the WES approach, we identified two novel, not yet reported, variants in the Slovak population of X-SCID patients. These findings strengthen the fact that rapid and comprehensive molecular-genetic diagnostics of IEI is necessary for the early definition of precise diagnosis, which further enables appropriate treatment and patient management.
X连锁重症联合免疫缺陷病（X-SCID）是一种与该基因的致病性DNA变异相关的先天性免疫缺陷（IEI）形式。X-SCID患者的特征是细胞免疫和体液免疫缺陷并存，且易感染。本文报告的病例为两名来自斯洛伐克人群的无关男性患者。先证者A在三个月大时因反复发热、呕吐和嗜睡首次住院，其非典型免疫表型被确定为T-B-NK-。先证者B在八个月大时因全身性脓疱性皮炎首次住院。对于未明确诊断的IEI患者，采用综合方法进行全外显子测序（WES），并通过桑格测序确认致病性DNA变异。对先证者的WES分析在该基因中鉴定出目前未描述的半合子变异p.Asn84Thr和p.Val213Ala。p.Asn84Thr的分离分析表明其为新发突变，而p.Val213Ala仅在无症状先证者的母亲中检测到。我们基于生物学和临床方面对这两个变异进行了全面重新评估和评分。最后，综合所有信息，根据美国医学遗传学与基因组学学会（ACMG）关于计算预测、临床相关性、功能位点定位和新发状态的标准，我们将p.Asn84Thr分类为可能致病，将p.Val213Ala分类为可能致病但外显率较低。通过WES方法，我们在斯洛伐克X-SCID患者群体中鉴定出两个尚未报道的新变异。这些发现强化了一个事实，即对IEI进行快速全面的分子遗传学诊断对于早期明确精确诊断是必要的，这进而能够实现适当的治疗和患者管理。
