Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Basic Science Article
  • Published:

Congenital and infantile nephrotic syndrome: genotype-phenotype associations

Pediatric Research (2025)Cite this article

Abstract

Background

Congenital nephrotic syndrome (CNS) and infantile nephrotic syndrome (INS) are disorders of podocytes in the slit diaphragm. CNS manifests during the first three months of life, and INS between 3–12 months, with severe proteinuria due to mutations in the NPHS1 and NPHS2 genes. This study aimed to establish specific genotype-phenotype characteristics of CNS and INS in the North American population.

Methods

Eleven Pediatric Nephrology Research Consortium (PNRC) sites retrospectively reviewed charts of 36 patients born between 1998–2019 who had CNS or INS and underwent genetic testing. The genetic database confirmed the variant’s pathogenicity.

Results

NPHS1 mutations were more frequently seen in CNS patients, while variant mutations in the WT1 and NPHS2 genes were more common in the INS group. Like c.2335-1 G > A splice mutation, the frequent compound heterozygous mutations of the NPHS1 gene were associated with more severe proteinuria (112.4 ± 135.6 vs. 53.9 ± 57.3). Additionally, NPHS1/WT1 and NPHS1/NPHS2 digenic inheritance featuring biallelic or tri-allelic hits were associated with patient transplantation, regardless of the disease onset.

Conclusion

Identification of compound heterozygous mutations in the NPHS1 gene as an indicator of an aggressive course of CNS in infants. This finding could lead to earlier and targeted interventions of patients, through a precision therapeutic approach

Impact

  • Variations at splice sites, particularly the c.2335-1 G > A mutation, alongside compound heterozygous mutations in the gene NPHS1 and digenic inheritance involving both NPHS1/WT1 or NPHS1/ NPHS2 with a triallelic hit, have been linked to a more severe progression of Congenital Nephrotic Syndrome (CNS) in infants.

  • The presence of a variant involving the digenic inheritance of the NPHS1 gene among children in North America suggests earlier indicators for the severity of the kidney disease.

  • This knowledge can transform the management of Congenital Nephrotic Syndrome in children’s healthcare settings, and lead to the development of early diagnosis biomarkers for the disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Mutation landscape of NPHS1, NPHS2 and WT1 gene in CNS and INS patients.
Fig. 2: Distribution of mutation characteristics and associated clinical parameters in CNS and INS patients.

Similar content being viewed by others

Data availability

The genetic data are available in the ClinVar Database (SCV004123127 - SCV004123153). Apart from this, all other data generated and analyzed during the current study are available from the corresponding author upon reasonable request.

References

  1. Zuo C., Z. J. Congenital Nephrotic Syndrome, https://www.pathologyoutlines.com/topic/kidneycongenitalnephroticsyndrome.html (2023).

  2. Hamasaki, Y. et al. A Cross-Sectional Nationwide Survey of Congenital and Infantile Nephrotic Syndrome in Japan. BMC Nephrol. 21, 363 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Niaudet, P. Congenital and Infantile Nephrotic Syndrome. Nephrol. Ther. 1, 63–70 (2005).

    Article  PubMed  Google Scholar 

  4. Bassanese, G. et al. The European Rare Kidney Disease Registry (ERKREG): Objectives, Design and Initial Results. Orphanet J. Rare Dis. 16, 251 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Bolk, S., Puffenberger, E. G., Hudson, J., Morton, D. H. & Chakravarti, A. Elevated Frequency and Allelic Heterogeneity of Congenital Nephrotic Syndrome, Finnish Type, in the Old Order Mennonites. Am. J. Hum. Genet. 65, 1785–1790 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kestila, M. et al. Positionally Cloned Gene for a Novel Glomerular Protein-Nephrin-Is Mutated in Congenital Nephrotic Syndrome. Mol. Cell 1, 575–582 (1998).

    Article  CAS  PubMed  Google Scholar 

  7. Toubiana, J. et al. Therapy-resistant anaemia in congenital nephrotic syndrome of the finnish type-implication of Epo, Transferrin and Transcobalamin losses. Nephrol. Dial. Transpl. 24, 1338–1340 (2009).

    Article  CAS  Google Scholar 

  8. Kandasamy, Y., Smith, R., Lumbers, E. R. & Rudd, D. Nephrin - a biomarker of early glomerular injury. Biomark. Res 2, 21 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Donoviel, D. B. et al. Proteinuria and perinatal lethality in mice lacking Neph1, a novel protein with homology to nephrin. Mol. Cell Biol. 21, 4829–4836 (2001).

    Article  CAS  PubMed Central  Google Scholar 

  10. Machuca, E. et al. Genotype-phenotype correlations in non-Finnish congenital nephrotic syndrome. J. Am. Soc. Nephrol. 21, 1209–1217 (2010).

    Article  CAS  Google Scholar 

  11. Ovunc, B. et al. Mutation analysis of Nphs1 in a worldwide cohort of congenital nephrotic syndrome patients. Nephron. Clin. Pr. 120, c139–c146 (2012).

    Article  CAS  Google Scholar 

  12. Schoeb, D. S. et al. Nineteen Novel Nphs1 mutations in a worldwide cohort of patients with congenital nephrotic syndrome (CNS). Nephrol. Dial. Transpl. 25, 2970–2976 (2010).

    Article  CAS  Google Scholar 

  13. Heeringa, S. F. et al. Thirteen Novel Nphs1 mutations in a large cohort of children with congenital nephrotic syndrome. Nephrol. Dial. Transpl. 23, 3527–3533 (2008).

    Article  CAS  Google Scholar 

  14. Yoshida, S. et al. Endoplasmic Reticulum-Associated Degradation Is Required for Nephrin Maturation and Kidney Glomerular Filtration Function. J. Clin. Invest. 131 (2021).

  15. Fu, R. et al. Novel Nphs1 splice site mutations in a Chinese child with congenital nephrotic syndrome. Genet Mol. Res 14, 433–439 (2015).

    Article  CAS  PubMed  Google Scholar 

  16. Abid, A. et al. Screening of the Lamb2, Wt1, Nphs1, and Nphs2 genes in pediatric nephrotic syndrome. Front Genet 9, 214 (2018).

    Article  PubMed  Google Scholar 

  17. Koziell, A. et al. Genotype/phenotype correlations of Nphs1 and Nphs2 mutations in nephrotic syndrome advocate a functional inter-relationship in glomerular filtration. Hum. Mol. Genet. 11, 379–388 (2002).

    Article  CAS  Google Scholar 

  18. Martin, C. E. & Jones, N. Nephrin signaling in the podocyte: an updated view of signal regulation at the slit diaphragm and beyond. Front Endocrinol. 9, 302 (2018).

    Article  Google Scholar 

  19. Gigante, M., Piemontese, M., Gesualdo, L., Iolascon, A. & Aucella, F. Molecular and genetic basis of inherited nephrotic syndrome. Int J. Nephrol. 2011, 792195 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Ettou, S. et al. Epigenetic transcriptional reprogramming by Wt1 mediates a repair response during podocyte injury. Sci. Adv. 6, eabb5460 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Guo, G., Morrison, D. J., Licht, J. D. & Quaggin, S. E. Wt1 activates a glomerular-specific enhancer identified from the human nephrin gene. J. Am. Soc. Nephrol. 15, 2851–2856 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Jeanpierre, C. et al. Identification of constitutional Wt1 mutations, in patients with isolated diffuse mesangial sclerosis, and analysis of genotype/phenotype correlations by use of a computerized mutation database. Am. J. Hum. Genet 62, 824–833 (1998).

    Article  CAS  PubMed  Google Scholar 

  23. Schumacher, V. et al. Spectrum of early onset nephrotic syndrome associated with Wt1 Missense mutations. Kidney Int. 53, 1594–1600 (1998).

    Article  CAS  Google Scholar 

  24. Lee, J. H. et al. Genetic basis of congenital and infantile nephrotic syndromes. Am. J. Kidney Dis. 58, 1042–1043 (2011).

    Article  Google Scholar 

  25. Hinkes, B. G. et al. Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 Genes (Nphs1, Nphs2, Wt1, and Lamb2). Pediatrics 119, e907–e919 (2007).

    Article  PubMed  Google Scholar 

  26. Vazquez Fonseca, L. et al. Mutations in Coq8b (Adck4) found in patients with steroid-resistant nephrotic syndrome alter Coq8b function. Hum. Mutat. 39, 406–414 (2018).

    Article  CAS  PubMed  Google Scholar 

  27. Liu, Y. et al. Clinical diagnosis of genetic disorders at both single-nucleotide and chromosomal levels based on the BGI Seq-500 Platform. Hum. Genome Var. 10, 15 (2023).

    Article  CAS  PubMed  Google Scholar 

  28. Braun, D. A. et al. Mutations in nuclear Pore Genes Nup93, Nup205, and Xpo5 cause steroid-resistant nephrotic syndrome. Nat. Genet. 48, 457–465 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Li, Y., Tian, C., Wang, Y., Ma, G. & Chen, R. Isolated steroid-resistant nephrotic syndrome in a Chinese child carrying a De Novo mutation in Wt1 Gene: A case report and literature review. BMC Pediatr. 22, 349 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Boyer, O. et al. Publisher correction: management of congenital nephrotic syndrome: consensus recommendations of the Erknet-Espn Working Group. Nat. Rev. Nephrol. 17, 434 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Constantinescu, A. R. et al. Clinical presentation and management of nephrotic syndrome in the first year of life: a report from the Pediatric Nephrology Research Consortium. Front Pediatr. 10, 988945 (2022).

    Article  PubMed  Google Scholar 

  32. UniProt, C. Uniprot: The Universal Protein Knowledgebase in 2023. Nucleic Acids Res. 51, D523–D531 (2023).

    Article  Google Scholar 

  33. Konc, J., Skrlj, B., Erzen, N., Kunej, T. & Janezic, D. Genprobis: web server for mapping of sequence variants to protein binding sites. Nucleic Acids Res. 45, W253–W259 (2017).

    Article  CAS  PubMed Central  Google Scholar 

  34. Hampel, H. et al. A Practice Guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: Referral Indications for Cancer Predisposition Assessment. Genet Med 17, 70–87 (2015).

    Article  PubMed  Google Scholar 

  35. Genomes Project, C. et al. A global reference for human genetic variation. Nature 526, 68–74 (2015).

    Article  Google Scholar 

  36. Stenson, P. D. et al. The Human Gene Mutation Database: Towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Hum. Genet. 136, 665–677 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Landrum, M. J. et al. Clinvar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res. 42, D980–D985 (2014).

    Article  CAS  PubMed  Google Scholar 

  38. Schwarz, J. M., Cooper, D. N., Schuelke, M. & Seelow, D. Mutationtaster2: Mutation prediction for the deep-sequencing age. Nat. Methods 11, 361–362 (2014).

    Article  CAS  PubMed  Google Scholar 

  39. Jaganathan, K. et al. Predicting splicing from primary sequence with deep learning. Cell 176, 535–548 e524 (2019).

    Article  CAS  PubMed  Google Scholar 

  40. Berody, S. et al. Treatment and outcome of congenital nephrotic syndrome. Nephrol. Dial. Transpl. 34, 458–467 (2019).

    Article  CAS  Google Scholar 

  41. Sharief, S. N. et al. Genetics of congenital and infantile nephrotic syndrome. World J. Pediatr. 15, 198–203 (2019).

    Article  CAS  PubMed  Google Scholar 

  42. Vachvanichsanong, P., Mitarnun, W., Tungsinmunkong, K. & Dissaneewate, P. Congenital and Infantile Nephrotic Syndrome in Thai Infants. Clin. Pediatr. 44, 169–174 (2005).

    Article  Google Scholar 

  43. Patrakka, J. et al. Congenital Nephrotic Syndrome (Nphs1): Features resulting from different mutations in Finnish Patients. Kidney Int. 58, 972–980 (2000).

    Article  CAS  Google Scholar 

  44. Xia, Z. J. et al. A dominant heterozygous mutation in Cog4 causes Saul-Wilson Syndrome, a primordial dwarfism, and disrupts Zebrafish development Via Wnt signaling. Front. Cell Dev. Biol. 9, 720688 (2021).

    Article  PubMed  Google Scholar 

  45. New, L. A., Keyvani Chahi, A. & Jones, N. Direct regulation of Nephrin Tyrosine phosphorylation by Nck adaptor proteins. J. Biol. Chem. 288, 1500–1510 (2013).

    Article  CAS  PubMed  Google Scholar 

  46. Guaragna, M. S. et al. Nphs2 mutations account for only 15% of nephrotic syndrome cases. BMC Med. Genet. 16, 88 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Al-Hamed, M. Sayer, J.A., Al-Hassoun, I., Aldahmesh, M.A. & Meyer, B. A novel mutation in Nphs2 causing nephrotic Syndrome in a Saudi Arabian family. NDT Plus 3, 545–548 (2010).

  48. Zlotogora, J. Multiple mutations responsible for frequent genetic diseases in isolated populations. Eur. J. Hum. Genet. 15, 272–278 (2007).

    Article  CAS  Google Scholar 

  49. Schaffer, A. A. Digenic inheritance in medical genetics. J. Med. Genet. 50, 641–652 (2013).

    Article  CAS  Google Scholar 

  50. Reynolds, B. C. & Oswald, R. J. A. Diagnostic and management challenges in congenital nephrotic syndrome. Pediatr. Health Med. Ther. 10, 157–167 (2019).

    Article  CAS  Google Scholar 

  51. Rong, L. et al. Genetic variations and clinical features of Nphs1-related nephrotic syndrome in Chinese Children: A multicenter, retrospective study. Front. Med. 8, 771227 (2021).

    Article  Google Scholar 

  52. Baumgartner-Parzer, S., Witsch-Baumgartner, M. & Hoeppner, W. Emqn best practice guidelines for molecular genetic testing and reporting of 21-Hydroxylase Deficiency. Eur. J. Hum. Genet. 28, 1341–1367 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Karamyshev, A. L. et al. Inefficient SRP interaction with a nascent chain triggers an mRNA quality control pathway. Cell 156, 146–157 (2014).

    Article  CAS  PubMed Central  Google Scholar 

  54. Anna, A. & Monika, G. Splicing mutations in human genetic disorders: examples, detection, and confirmation. J. Appl. Genet. 59, 253–268 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bullich, G. et al. A kidney-disease gene panel allows a comprehensive genetic diagnosis of cystic and glomerular inherited kidney diseases. Kidney Int. 94, 363–371 (2018).

    Article  Google Scholar 

Download references

Acknowledgements

The authors would like to thank the member of the Pediatric Nephrology Research Consortium for approval of this manuscript. The authors also appreciated Dr. Stephanie Stroever for her support of statistical analysis.

Funding

This research was funded by an institutional seed grant from Texas Tech University Health Sciences Center, TX, USA (Grant No. 182169 - 402611 - 20)

Author information

Authors and Affiliations

  1. Department of Pediatrics, Texas Tech University Health Sciences Center, Amarillo, TX, USA

    Md Saimul Islam & Tetyana L. Vasylyeva

  2. Department of Pediatrics, Joe DiMaggio Children’s Hospital, Hollywood, FL, USA

    Alexandru R. Constantinescu & Belkis Wandique Rapalo

  3. Center for Clinical and Translational Research, The Research Institute at Nationwide Children’s Hospital, The Ohio State University, Columbus, OH, USA

    William E. Smoyer

  4. Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA

    Tej K. Mattoo

  5. Department of Pediatrics, Division of Nephrology, Emory University, Atlanta, GA, USA

    Ali Abdullahi Annaim

  6. University of Minnesota, Minneapolis, MN, USA

    Emilee Plautz

  7. Division of Nephrology, Boston Children’s Hospital, Boston, MA, USA

    Liz Benoit

  8. Division of Nephrology, Department of Pediatrics, Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada

    Robert L. Myette

  9. Division of Pediatric Nephrology, The Ohio State University, Nationwide Children’s Hospital, Columbus, OH, USA

    Mahmoud Kallash

  10. Department of Pediatric Nephrology, Baylor College of Medicine, Houston, TX, USA

    Scott E. Wenderfer

  11. Acute Dialysis Units, Pediatric Kidney Transplant, Medical University of South Carolina, Charleston, SC, USA

    Katherine Twombley

  12. Center for Clinical and Translational Research, Nationwide Children’s Hospital, Columbus, OH, USA

    Yu Kamigaki

  13. Pediatric Nephrology, Children’s Hospital and Medical Center, Omaha, NE, USA

    Melissa Muff-Luett

  14. Division of Pediatric Nephrology, University of Minnesota, Minneapolis, MN, USA

    Michelle N. Rheault

Authors
  1. Md Saimul Islam
    View author publications

    Search author on:PubMed Google Scholar

  2. Alexandru R. Constantinescu
    View author publications

    Search author on:PubMed Google Scholar

  3. William E. Smoyer
    View author publications

    Search author on:PubMed Google Scholar

  4. Tej K. Mattoo
    View author publications

    Search author on:PubMed Google Scholar

  5. Ali Abdullahi Annaim
    View author publications

    Search author on:PubMed Google Scholar

  6. Emilee Plautz
    View author publications

    Search author on:PubMed Google Scholar

  7. Belkis Wandique Rapalo
    View author publications

    Search author on:PubMed Google Scholar

  8. Liz Benoit
    View author publications

    Search author on:PubMed Google Scholar

  9. Robert L. Myette
    View author publications

    Search author on:PubMed Google Scholar

  10. Mahmoud Kallash
    View author publications

    Search author on:PubMed Google Scholar

  11. Scott E. Wenderfer
    View author publications

    Search author on:PubMed Google Scholar

  12. Katherine Twombley
    View author publications

    Search author on:PubMed Google Scholar

  13. Yu Kamigaki
    View author publications

    Search author on:PubMed Google Scholar

  14. Melissa Muff-Luett
    View author publications

    Search author on:PubMed Google Scholar

  15. Michelle N. Rheault
    View author publications

    Search author on:PubMed Google Scholar

  16. Tetyana L. Vasylyeva
    View author publications

    Search author on:PubMed Google Scholar

Contributions

M.I. & T.V.: Conceived the idea and wrote the manuscript; A.C.: Collected and organized the patient’s data; M.N.R., W.S., T.M., A.A., E.P., B.R., L.B., R.M., M.K., S.W. & K.T.: Collected patient data; M.N.R., M.M., M.I. & Y.K.: carried out all data analysis; M.I., Y.K., M.M.; Wrote original draft, T.V., W.S., Y.K., A.R., T.M., S.W. & R.M.: Reviewed and made modifications to the article, T.V.: Supervised and acquired funding. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Tetyana L. Vasylyeva.

Ethics declarations

Competing interests

The authors declare no competing interests.

Consent statement

All the patients give written consent for this study as per local IRB of each institute.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Islam, M.S., Constantinescu, A.R., Smoyer, W.E. et al. Congenital and infantile nephrotic syndrome: genotype-phenotype associations. Pediatr Res (2025). https://doi.org/10.1038/s41390-025-04095-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • DOI: https://doi.org/10.1038/s41390-025-04095-w

Search

Advanced search

Quick links