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Factors predicting the occurrence of disease-causing variants on next-generation sequencing in children with steroid-resistant nephrotic syndrome — implications for resource-constrained settings

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Abstract

Background

Enhanced availability of high-throughput sequencing (at progressively reducing costs) has revolutionized the identification of monogenic SRNS. However, in resource-poor settings, it may not be possible to perform next-generation sequencing (NGS) in all children wherein monogenic SRNS is suspected. Besides, the optimal strategy of genetic evaluation (in patients with SRNS) in routine clinical practice in resource-limited settings is unknown.

Methods

Patients with newly diagnosed SRNS were recruited from our center and followed up prospectively. We analyzed the factor(s) independently predicting the occurrence of disease-causing variants in these patients.

Results

In our study, 36 children/adolescents with SRNS were included (initial steroid resistance in 53%). On targeted NGS, pathogenic/likely pathogenic variants were identified in 31% (n = 11). These included homozygous or compound heterozygous variants in the following genes: ALOX12B, COL4A3, CRB2, NPHS1, NPHS2, PLCE1, and heterozygous variant in WT1 gene. Overall, 14 variants were identified of which 5 (36%) were novel. Age of < 1 or < 2 years and presence of family history of nephrotic syndrome independently predicted the occurrence of monogenic SRNS on multivariate analysis.

Conclusions

While NGS-based genetic testing in SRNS is increasingly being incorporated in routine clinical practice the world over, the scenario is far from optimal in resource-limited settings. Our study highlights that resources for genetic testing in SRNS should be prioritized for patients with early age at disease onset and presence of family history. Larger studies composed of diverse multi-ethnic cohorts of patients with SRNS are required to further delineate the optimal strategy of genetic evaluation in resource-poor settings.

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Data availability

Relevant data utilized in the preparation of this manuscript are provided in the main manuscript and supplementary tables. Additional data underlying this article will be shared on reasonable request to the corresponding author.

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Acknowledgements

We sincerely thank the clinical and nursing staff who provided their valuable help in patient management and follow-up.

Funding

Intramural institutional grant (from authors’ institution – Post Graduate Institute of Medical Education and Research, Chandigarh, India).

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Author notes

  1. Anit Kaur and Aaqib Zaffar Banday contributed equally and qualify as joint first authors.

Authors and Affiliations

  1. Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Center, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

    Anit Kaur, Aaqib Zaffar Banday & Amit Rawat

  2. Nephrology Unit, Department of Pediatrics, Advanced Pediatrics Center, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India

    Lesa Dawman & Karalanglin Tiewsoh

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  1. Anit Kaur
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Contributions

AK, AZB: Acquisition, analysis, and interpretation of data; drafted, edited, and critically revised the manuscript.

LD, AR: Patient management and follow-up; analysis and interpretation of data; edited and critically revised the manuscript.

KT: Patient management and follow-up; conception of idea and design of the study; acquisition, analysis, and interpretation of data; edited and critically revised the manuscript; overall supervision.

All co-authors approve the final version of the manuscript and take full responsibility for the integrity and accuracy of all aspects of the study.

Corresponding author

Correspondence to Karalanglin Tiewsoh.

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Ethical approval and informed consent

This study is approved by the Institutional Ethics Committee of Post Graduate Institute of Medical Education and Research, Chandigarh, India vide INT/IEC/2019/000635. Informed consent was obtained from patient’s caregivers/parents before inclusion in the study.

Conflict of interest

The authors declare no competing interests.

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Kaur, A., Banday, A.Z., Dawman, L. et al. Factors predicting the occurrence of disease-causing variants on next-generation sequencing in children with steroid-resistant nephrotic syndrome — implications for resource-constrained settings. Pediatr Nephrol 38, 3663–3670 (2023). https://doi.org/10.1007/s00467-023-06042-5

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