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

Mansour B 1 , Lemberg K 1 , Schneider R 1 , Saida K 1 , Elmubarak I 1 , Yu S 1 Show all authors , Yousef K 1 , Nicolas Frank C 1 , Riedhammer KM 1 , Zahoor MY 1 , Kolvenbach CM 1 , Merz LM 1 , Mertens ND 1 , Bao A 1 , Salmanullah D 1 , Kalkar G 1 , Hölzel S 1 , Zion E 1 , Marchuk D 1 , Lomjansook K 1 , Braun A 1 , Franken GAC 1 , Eid LA 2 , Awad HSH 2 , Al Saffar M 1 , Soliman NA 3 , Nabhan MM 3 , Kari JA 4 , El Desoky S 4 , Shalaby MA 4 , Ooda S 5 , Fathy HM 6 , Mane S 7 , Shril S 1 , Somers MJG 1 , Buerger F 1 , Hildebrandt F 8

Affiliations 

  • 1 Department of Pediatrics, Division of Nephrology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, 02115 MA, USA
  • 2 Kidney Centre of Excellence, Al Jalila Children's Specialty Hospital, Dubai, United Arab Emirates
  • 3 Department of Pediatrics, Center for Pediatric Nephrology and Transplantation, Kasr Al Ainy Medical School, Cairo University, Cairo, Egypt
  • 4 Pediatric Nephrology Center of Excellence, Department of Pediatrics, Faculty of Medicine, King Abdulaziz University Hospital, King Abdulaziz University, Jeddah, Saudi Arabia
  • 5 Experimental and Clinical Internal Medicine Department, Medical Research Institute, Alexandria University, Alexandria, Egypt
  • 6 Department of Pediatrics, Alexandria Faculty of Medicine, Alexandria University, Alexandria, Egypt
  • 7 Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
  • 8 Department of Pediatrics, Division of Nephrology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, 02115 MA, USA. friedhelm.hildebrandt@childrens.harvard.edu
Pediatr Nephrol, 2026 Jun;41(6):1663-1675.
PMID: 41575523 DOI: 10.1007/s00467-026-07151-7

Abstract

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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