Soliman Neveen A, Elmonem Mohamed A, El-Sayed Ahmed F, Ramadan Eman, Badr Ahmed M, Atia Fatma M, Helmy Rasha, Amer May O, El-Raouf Ahmed Abd, El-Garhy Fadya M, Abdel-Haseb Omnia M, Hassan Tokka M, Farouk Yasmeen K, El-Hosseiny Ahmed, Bakry Usama, Ali Asmaa, Saleeb Sheri, Ghanim Tasnim A, Albarbary Mahynour, Elmahy Ahmed, Elnagdy Tarek, Ragheb Amira, Hassan Wael A, Moustafa Ahmed, Amer Khaled
Department of Pediatrics, Center of Pediatric Nephrology and Transplantation (CPNT), Faculty of Medicine, Cairo University, Cairo, Egypt.
Egypt Center for Research and Regenerative Medicine (ECRRM), Cairo, Egypt.
Hum Genet. 2025 May 22. doi: 10.1007/s00439-025-02752-y.
Genetic causes of steroid-resistant-nephrotic-syndrome (SRNS) represent a rapidly growing number of monogenic diseases. The reported diagnostic yield of various studies applying genetic panels and exome-sequencing to diagnose SRNS is usually < 30%. We performed genome-sequencing in a cohort of Egyptian SRNS patients. We recruited 47 SRNS patients belonging to 41 unrelated families [28 males/19 females; median (range): 6 (0.5-22 years)]. We established a pipeline for genome sequencing, bioinformatics analysis, variant curation and protein modeling at the Egypt Center for Research and Regenerative Medicine (ECRRM). Disease-causing variants were detected in 27/47 patients (57.4%) belonging to 23/41 families (56.1%), including nine novel variants in NPHS1, NPHS2, COL4A3, MYO1E, NUP93, PLCE1, PODXL, SMARCAL1 and WT1. Novel variants were confirmed by Sanger sequencing and were segregated in families of affected patients. NPHS2 was the most common causative gene in 8/23 (34.8%) of confirmed families, followed by NPHS1, WT1, and SMARCAL1 in 2/23 families (8.7%) each. All detected missense variants were evaluated through protein modeling and were predicted deleterious. Our study expanded the spectrum of SRNS disease-causing variants and revealed a monogenic cause in 56.1% of investigated families. In our cohort, no deep intronic or regulatory variants were detected by genome-sequencing. Pursuing genetic diagnosis in SRNS patients is crucial to inform clinical decision making, genetic counseling, transplantation strategy and prenatal diagnosis thus improving clinical outcome of affected patients.
类固醇抵抗性肾病综合征（SRNS）的遗传病因代表了数量迅速增长的单基因疾病。应用基因检测板和外显子组测序诊断SRNS的各种研究报告的诊断率通常<30%。我们对一组埃及SRNS患者进行了全基因组测序。我们招募了47名SRNS患者，他们来自41个无亲缘关系的家庭[28名男性/19名女性；中位数（范围）：6（0.5 - 22岁）]。我们在埃及研究与再生医学中心（ECRRM）建立了一个全基因组测序、生物信息学分析、变异筛选和蛋白质建模的流程。在47名患者中的27名（57.4%）、41个家庭中的23个（56.1%）检测到致病变异，包括NPHS1、NPHS2、COL4A3、MYO1E、NUP93、PLCE1、PODXL、SMARCAL1和WT1中的9个新变异。新变异通过桑格测序得到确认，并在受影响患者的家庭中进行了分离分析。NPHS2是8/23（34.8%）个确诊家庭中最常见的致病基因，其次是NPHS1、WT1和SMARCAL1，各占2/23个家庭（8.7%）。所有检测到的错义变异都通过蛋白质建模进行了评估，并被预测为有害变异。我们的研究扩展了SRNS致病变异的谱图，并在56.1%的被调查家庭中揭示了单基因病因。在我们的队列中，通过全基因组测序未检测到深层内含子或调控变异。对SRNS患者进行基因诊断对于指导临床决策、遗传咨询、移植策略和产前诊断至关重要，从而改善受影响患者的临床结局。
