GENETIC BASIS OF STEROID-RESISTANT NEPHROTIC SYNDROME IN CHILDREN AND CLINICAL CORRELATES
Keywords:
steroid-resistant nephrotic syndrome; NGS; COL4A; Alport syndrome; pediatric nephrologyAbstract
Introduction. Steroid-resistant nephrotic syndrome (SRNS) carries a high risk of progression to end-stage renal disease. Next-generation sequencing (NGS) has shown that a significant proportion of pediatric cases have a monogenic cause, with direct implications for therapy and prognosis.
Aim. To characterize the mutational spectrum of pediatric SRNS and congenital nephrotic syndrome (CNS) in a National children’s medical center cohort and examine genotype–phenotype associations.
Methods. 54 pediatric patients with confirmed SRNS or CNS underwent targeted NGS panel testing. Associations were assessed using Mann-Whitney U, chi-square, and Fisher’s exact tests.
Results. A total of 54 pediatric patients with genetically confirmed SRNS or CNS were included to the study. 34 distinct genetic entities were identified. COL4A-family mutations (COL4A3/4/5) were the most prevalent category (27.8%), with COL4A5 being the single most common gene (14.8%) and showing significant male predominance (M:F = 7:1; OR = 4.32, p = 0.038). CNS patients were significantly younger than SRNS patients (p = 0.022). COQ2 mutations accounted for 5.6%, all presenting as CNS. Digenic mutations were found in 20.4% of patients.
Conclusion. COL4A mutations dominate pediatric SRNS genetics, contrasting with NPHS2 predominance in Western cohorts. Comprehensive genetic panel testing should be standard of care in all pediatric SRNS patients.
References
Trautmann A, Vivarelli M, Samuel S, et al. IPNA clinical practice recommendations for the diagnosis and management of children with steroid-resistant nephrotic syndrome. Pediatr Nephrol. 2020;35(6):1529–1561.
Bierzynska A, Soderquest K, Koziell A. Genes and podocytes - new insights into mechanisms of podocytopathy. Front Endocrinol. 2017;7:186.
Vivante A, Hildebrandt F. Exploring the genetic basis of early-onset chronic kidney disease. Nat Rev Nephrol. 2016;12(3):133–146.
Lovric S, Ashraf S, Tan W, Hildebrandt F. Genetic testing in steroid-resistant nephrotic syndrome: when and how? Nephrol Dial Transplant. 2016;31(11):1802–1813.
Nagano C, Yamamura T, Horinouchi T, et al. Comprehensive genetic diagnosis of Japanese patients with severe proteinuria. Sci Rep. 2020;10(1):11285.
Daga S, Donati F, Capitani K, et al. New frontiers to cure Alport syndrome: COL4A3 and COL4A4 mutations sorted by predicted protein structural-functional alterations. J Nephrol. 2021;34(4):1104–1115.
Gast C, Pengelly RJ, Lyon M, et al. Collagen (COL4A) mutations are the most frequent mutations underlying adult focal segmental glomerulosclerosis. Nephrol Dial Transplant. 2016;31(6):961–970.
Wang F, Zhang Y, Mao J, et al. Spectrum of mutations in Chinese children with steroid-resistant nephrotic syndrome. Pediatr Nephrol. 2017;32(7):1207–1221.
Sadowski CE, Lovric S, Ashraf S, et al. A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome. J Am Soc Nephrol. 2015;26(6):1279–1289.
Büscher AK, Habbig S, Kranz B, et al. Loss-of-function mutations in ITSN2 cause autosomal recessive nephrotic syndrome. Kidney Int. 2022;101(3):569–580.
