Novel mutation patterns in children with steroid-resistant nephrotic syndrome

Narayan Prasad; Jeyakumar Meyyappan; Manoj Dhanorkar; Ravi Kushwaha; Kausik Mandal; Vamsidhar Veeranki; Manas Behera; Manas Patel; Brijesh Yadav; Dharmendra Bhadauria; Anupama Kaul; Monika Yaccha; Mansi Bhatt; Vinita Agarwal; Monoj Jain

doi:10.1093/ckj/sfae218

Novel mutation patterns in children with steroid-resistant nephrotic syndrome

Clin Kidney J. 2024 Jul 23;17(8):sfae218. doi: 10.1093/ckj/sfae218. eCollection 2024 Aug.

Authors

Affiliations

¹ Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.
² Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.
³ Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.

Abstract

Background: Idiopathic nephrotic syndrome (NS) in children poses treatment challenges, with a subset developing steroid-resistant nephrotic syndrome (SRNS). Genetic factors play a role, yet data on paediatric SRNS genetics in India are scarce. We conducted a prospective study using whole-exome sequencing to explore genetic variants and their clinical correlations.

Methods: A single-centre prospective study (October 2018-April 2023) enrolled children with SRNS, undergoing renal biopsy and genetic testing per institutional protocol. Clinical, histological, and genetic data were recorded. DNA isolation and next-generation sequencing were conducted for genetic analysis. Data collection included demographics, clinical parameters, and kidney biopsy findings. Syndromic features were evaluated, with second-line immunosuppressive therapy administered. Patient and renal outcomes are presented for patients with and without genetic variants.

Results: A total of 680 paediatric NS patients were analysed, with 121 (17.8%) having SRNS and 96 consent to genetic analysis. 69 (71.9%) had early SRNS, 27 (28.1%) late. Among participants, 62 (64.58%) had reportable genetic variants. The most common were in COL4A genes, with 20 (31.7%) positive. Renal biopsy showed focal segmental glomerulosclerosis in 31/42 (74%) with variants, 16/28 (57.1%) without variants. Second-line immunosuppressions varied, with CNIs the most common. Outcomes varied, with partial or complete remission achieved in some while others progressed to ESRD.

Conclusion: The study underscores the importance of genetic analysis in paediatric SRNS, revealing variants in 65.7% of cases. COL4A variants were predominant. Variants correlated with varied renal outcomes, highlighting potential prognostic implications. These findings emphasize the value of personalized approaches and further research in managing paediatric SRNS.

Keywords: COL4A mutations; SRNS; genotype–phenotype correlations; paediatric nephrotic syndrome; whole-exome sequencing.