Li Sheng, Hu Miaoyue, He Chao, Sun Yu, Huang Weifang, Lei Fengying, Liu Yunguang, Huang Zengpo, Meng Yongqiu, Liu Wenjing, Lei Xianqiang, Dong Yanfang, Lin Zihui, Huang Chunlin, Zhao Rihong, Qin Yuanhan
Department of Pediatrics, The First Hospital of Guangxi Medical University, Nanning, China.
Department of Pediatrics, The First Affiliated Hospital of University of South China, Hengyang, China.
PLoS One. 2024 Dec 3;19(12):e0304864. doi: 10.1371/journal.pone.0304864. eCollection 2024.
This study aimed to discuss the pathogenic hereditary factors of children with steroid-resistant nephrotic syndrome (SRNS) in Guangxi, China. We recruited 89 patients with SRNS or infantile NS from five major pediatric nephrology centers in Guangxi, and conducted a retrospective analysis of clinical data. Whole-exome sequencing analysis was also performed on all patients. The risk of progression to chronic kidney disease (CKD) was assessed using the Kaplan-Meier method and Cox proportional hazards model. The study included 69 male and 20 female participants from 86 distinct families, with the median age of disease onset being 48 months (interquartile range: 24-93). Overall, 24.7% had a family history of SRNS, whereas 13.5% exhibited extra-kidney manifestations. We identified disease-causing variants in 24.7% (22/89) of patients across eight screened genes. The most frequently detected variant was found in COL4A5, followed by NPHS2 (5.6%), NPHS1 (2.2%), PAX2 (2.2%), WT1 (1.1%), LMX1B (1.1%), NUP105 (1.1%), and COL4A6 (1.1%). Twelve of the 26 pathogenic variants were determined to be de novo. Based on gene detection results, pathogenic variants were categorized into two groups: identified and unidentified variants. The identified variant group demonstrated a significant association with positive family history, steroid resistant-style, and response to immune therapy (P<0.001). Patients with the identified genetic variant were approximately ten times more likely to develop CKD (P<0.001) than those in the unidentified group at the last follow-up. Kidney biopsy was performed on 66 patients, and minimal change disease was the most prevalent histopathological diagnosis (29 cases; 32.6%). These findings suggest that children diagnosed with SRNS exhibit a diverse range of genetic alterations. We identified the COL4A5 variant as the predominant genetic abnormality and a low frequency of NPHS1 gene involvement in these children. Gene variants may serve as an independent predictor for SRNS progression to CKD.
本研究旨在探讨中国广西地区激素抵抗型肾病综合征（SRNS）患儿的致病遗传因素。我们从广西五大儿科肾病中心招募了89例SRNS或婴儿型肾病综合征患者，并对临床资料进行回顾性分析。同时对所有患者进行全外显子测序分析。采用Kaplan-Meier法和Cox比例风险模型评估进展为慢性肾脏病（CKD）的风险。该研究纳入了来自86个不同家庭的69名男性和20名女性参与者，疾病发病的中位年龄为48个月（四分位间距：24-93）。总体而言，24.7%的患者有SRNS家族史，而13.5%的患者表现出肾外表现。我们在8个筛查基因中，发现24.7%（22/89）的患者存在致病变异。最常检测到的变异位于COL4A5基因，其次是NPHS2（5.6%）、NPHS1（2.2%）、PAX2（2.2%）、WT1（1.1%）、LMX1B（1.1%）、NUP105（1.1%）和COL4A6（1.1%）。26个致病变异中有12个被确定为新发变异。根据基因检测结果，致病变异分为两组：已确定变异和未确定变异。已确定变异组与阳性家族史、激素抵抗类型及免疫治疗反应显著相关（P<0.001）。在最后一次随访时，携带已确定基因变异的患者发生CKD的可能性比未确定组患者高约10倍（P<0.001）。对66例患者进行了肾活检，微小病变病是最常见的组织病理学诊断（29例；32.6%）。这些发现表明，被诊断为SRNS的儿童表现出多种基因改变。我们确定COL4A5变异是主要的基因异常，且这些儿童中NPHS1基因受累频率较低。基因变异可能是SRNS进展为CKD的独立预测因素。
