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Background <p>Steroid-resistant nephrotic syndrome (SRNS) constitutes the second most common cause of chronic kidney disease (CKD) in children. A monogenic cause can be identified in approximately 25% of SRNS cases. In contrast, steroid-sensitive or steroid-dependent nephrotic syndrome (SSNS/SDNS) is typically attributed to multifactorial or immunological causes and rarely linked to monogenic etiology.</p> Methods <p>We performed exome sequencing (ES) in 237 families, including 183 with SRNS and 54 with SSNS/SDNS.</p> Results <p>A (likely) pathogenic variant in a known SRNS gene was identified in 29/183 individuals with SRNS (15.8%). Additionally, 6/183 (3.3%) individuals with SRNS carried pathogenic variants in phenocopy genes—genes associated with diseases that clinically mimic SRNS. The diagnostic yield was significantly higher in individuals with ≥ 50&#xa0;Mb homozygosity-by-descent (HBD) (44.7% vs. 8.5%) and in those with SRNS disease onset before 1 year of age (41.9%). In individuals with SSNS/SDNS, we found a likely causative variant in only 1 of 54 probands.</p> Conclusions <p>A genetic cause was established in 19.1% of SRNS patients (15.8% in known SRNS genes and 3.3% in phenocopy genes), but only 1.9% of non-steroid-resistant cases.</p> Graphical Abstract <p>A higher resolution version of the Graphical abstract is available as <InternalRef RefID="MOESM2">Supplementary information</InternalRef>.</p> <p></p>

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Identification of monogenic variants in steroid-resistant and steroid-sensitive nephrotic syndrome

  • 期刊论文

  • 发表日期：

    2026年1月23日

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  • Bshara Mansour,
  • Katharina Lemberg,
  • Ronen Schneider,
  • Ken Saida,
  • Izzeldin Elmubarak,
  • Seyoung Yu,
  • Kirollos Yousef,
  • Camille Nicolas Frank,
  • Korbinian M. Riedhammer,
  • Muhammad Yasir Zahoor,
  • Caroline M. Kolvenbach,
  • Lea M. Merz,
  • Nils D. Mertens,
  • Aaron Bao,
  • Daanya Salmanullah,
  • Gina Kalkar,
  • Selina Hölzel,
  • Elena Zion,
  • Daniel Marchuk,
  • Kraisoon Lomjansook,
  • Alina Braun,
  • Gijs A. C. Franken,
  • Loai A. Eid,
  • Hazem Subhi H. Awad,
  • Muna Al Saffar,
  • Neveen A. Soliman,
  • Marwa M. Nabhan,
  • Jameela A. Kari,
  • Sherif El Desoky,
  • Mohamed A. Shalaby,
  • Said Ooda,
  • Hanan M. Fathy,
  • Shrikant Mane,
  • Shirlee Shril,
  • Michael J. G. Somers,
  • Florian Buerger,
  • Friedhelm Hildebrandt

摘要

Background

Steroid-resistant nephrotic syndrome (SRNS) constitutes the second most common cause of chronic kidney disease (CKD) in children. A monogenic cause can be identified in approximately 25% of SRNS cases. In contrast, steroid-sensitive or steroid-dependent nephrotic syndrome (SSNS/SDNS) is typically attributed to multifactorial or immunological causes and rarely linked to monogenic etiology.

Methods

We performed exome sequencing (ES) in 237 families, including 183 with SRNS and 54 with SSNS/SDNS.

Results

A (likely) pathogenic variant in a known SRNS gene was identified in 29/183 individuals with SRNS (15.8%). Additionally, 6/183 (3.3%) individuals with SRNS carried pathogenic variants in phenocopy genes—genes associated with diseases that clinically mimic SRNS. The diagnostic yield was significantly higher in individuals with ≥ 50 Mb homozygosity-by-descent (HBD) (44.7% vs. 8.5%) and in those with SRNS disease onset before 1 year of age (41.9%). In individuals with SSNS/SDNS, we found a likely causative variant in only 1 of 54 probands.

Conclusions

A genetic cause was established in 19.1% of SRNS patients (15.8% in known SRNS genes and 3.3% in phenocopy genes), but only 1.9% of non-steroid-resistant cases.

Graphical Abstract

A higher resolution version of the Graphical abstract is available as Supplementary information.