Background: Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of end-stage renal disease (ESRD) among patients manifesting at under 25 years of age. We performed mutation analysis using a high-throughput PCR-based microfluidic technology in 24 single-gene causes of SRNS in a cohort of 72 families, who presented with SRNS before the age of 25 years. Methods: Within an 18-month interval, we obtained DNA samples, pedigree information, and clinical information from 77 consecutive children with SRNS from 72 different families seen at Boston Children’s Hospital (BCH). Mutation analysis was completed by combining high-throughput multiplex PCR with next-generation sequencing. We analyzed the sequences of 18 recessive and 6 dominant genes of SRNS in all 72 families for disease-causing variants. Results: We identified the disease-causing mutation in 8 out of 72 (11.1%) families. Mutations were detected in the six genes: NPHS1 (2 out of 72), WT1 (2 out of 72), NPHS2, MYO1E, TRPC6, and INF2. Median age at onset was 4.1 years in patients without a mutation (range 0.5–18.8), and 3.2 years in those in whom the causative mutation was detected (range 0.1–14.3). Mutations in dominant genes presented with a median onset of 4.5 years (range 3.2–14.3). Mutations in recessive genes presented with a median onset of 0.5 years (range 0.1–3.2). Conclusion: Our molecular genetic diagnostic study identified underlying monogenic causes of steroid-resistant nephrotic syndrome in ~11% of patients with SRNS using a cost-effective technique. We delineated some of the therapeutic, diagnostic, and prognostic implications. Our study confirms that genetic testing is indicated in pediatric patients with SRNS.
Bibliographical noteFunding Information:
Acknowledgements We thank the physicians and the participating families for their contribution. FH is the William E. Harmon Professor of Pediatrics. This research was supported by grants from the National Institutes of Health (DK076683 to FH). WT is supported by the NIH T32 Training grant (DK007726) and the ASN Benjamin J. Lipps Research Fellowship Award (FP01014311). EW is supported by the Leopoldina Fellowship Program, German National Academy of Sciences Leopoldina (LPDS 2015-07).
© 2017, IPNA.
All Science Journal Classification (ASJC) codes
- Pediatrics, Perinatology, and Child Health