Dashti Mohammed, AlKandari Hessa, Malik Md Zubbair, Nizam Rasheeba, John Sumi Elsa, Jacob Sindhu, Channanath Arshad, Othman Fouzeyah, Al-Sayed Safa, Al-Hindi Osama, Al-Mutari Mona, Thanaraj Thangavel Alphonse, Al-Mulla Fahd
Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Kuwait City, Kuwait.
Department of Population Health, Dasman Diabetes Institute, Kuwait City, Kuwait.
Front Cell Infect Microbiol. 2025 Jan 8;14:1444216. doi: 10.3389/fcimb.2024.1444216. eCollection 2024.
Multisystem inflammatory syndrome in children (MIS-C) is a severe complication arising from SARS-CoV-2 infection, with indications that rare inborn errors of immunity may play a role in its pathogenesis. Recent studies suggest that genetic predispositions, particularly monogenic forms, could significantly influence the immune responses to SARS-CoV-2 in MIS-C.
We analysed 24 children under 12 years old, all of whom met the criteria provided by the World Health Organization, 2020 for MIS-C diagnosis, from the Paediatric COVID-19 Registry in Kuwait (PCR-Q8). Demographic and clinical data were collected from medical records, and exome sequencing was performed on the children and their parents to identify rare exonic variants. These variants were prioritized using two approaches: a candidate genes approach employing trio segregation analysis, and a candidate variants approach using a gene panel informed by previous studies on MIS-C-related genetic variants and datasets of differentially expressed genes in MIS-C patients.
The candidate genes approach identified 53 unique genes in 20 of the 24 probands, including and , which were also differentially expressed between MIS-C and control groups. The candidate variants approach identified 33 rare, predicted deleterious heterozygous variants across 19 unique genes in 19 of the 24 probands, including both previously described and novel candidate variants for MIS-C. Pathway analysis of the identified genes from both approaches revealed significant involvement in immune response, viral defence, and inflammatory pathways.
This study underscores the monogenic susceptibility to MIS-C, enhancing the evidence base through comprehensive genetic analysis. The findings highlight the critical role of genetic predispositions in MIS-C and suggest that further functional genomics work is necessary to explore the mechanistic contributions of these genes, facilitating the development of targeted diagnostic strategies.
儿童多系统炎症综合征（MIS-C）是由严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染引起的一种严重并发症，有迹象表明罕见的先天性免疫缺陷可能在其发病机制中起作用。最近的研究表明，遗传易感性，尤其是单基因形式，可能会显著影响MIS-C患者对SARS-CoV-2的免疫反应。
我们分析了科威特儿科COVID-19登记处（PCR-Q8）的24名12岁以下儿童，他们均符合世界卫生组织2020年MIS-C诊断标准。从医疗记录中收集人口统计学和临床数据，并对这些儿童及其父母进行外显子组测序，以识别罕见的外显子变异。使用两种方法对这些变异进行优先级排序：一种是采用三联体分离分析的候选基因方法，另一种是使用基于先前关于MIS-C相关遗传变异的研究和MIS-C患者差异表达基因数据集的基因panel的候选变异方法。
候选基因方法在24名先证者中的20名中鉴定出53个独特基因，包括[具体基因1]和[具体基因2]，它们在MIS-C组和对照组之间也存在差异表达。候选变异方法在24名先证者中的19名中鉴定出19个独特基因中的33个罕见的、预测有害的杂合变异，包括先前描述的和新的MIS-C候选变异。两种方法鉴定出的基因的通路分析显示，它们显著参与免疫反应、病毒防御和炎症通路。
本研究强调了MIS-C的单基因易感性，通过全面的遗传分析增强了证据基础。研究结果突出了遗传易感性在MIS-C中的关键作用，并表明需要进一步开展功能基因组学工作，以探索这些基因的机制性贡献，促进靶向诊断策略的开发。
