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Copy number variation analysis in 138 families with steroid-resistant nephrotic syndrome identifies causal homozygous deletions in PLCE1 and NPHS2 in two families

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Abstract

Background

Steroid-resistant nephrotic syndrome (SRNS) is the second most common cause of kidney failure in children and adults under the age of 20 years. Previously, we were able to detect by exome sequencing (ES) a known monogenic cause of SRNS in 25–30% of affected families. However, ES falls short of detecting copy number variants (CNV). Therefore, we hypothesized that causal CNVs could be detected in a large SRNS cohort.

Methods

We performed genome-wide single nucleotide polymorphism (SNP)-based CNV analysis on a cohort of 138 SRNS families, in whom we previously did not identify a genetic cause through ES. We evaluated ES and CNV data for variants in 60 known SRNS genes and in 13 genes in which variants are known to cause a phenocopy of SRNS. We applied previously published, predefined criteria for CNV evaluation.

Results

We detected a novel CNV in two genes in 2 out of 138 families (1.5%). The 9,673 bp homozygous deletion in PLCE1 and the 6,790 bp homozygous deletion in NPHS2 were confirmed across the breakpoints by PCR and Sanger sequencing.

Conclusions

We confirmed that CNV analysis can identify the genetic cause in SRNS families that remained unsolved after ES. Though the rate of detected CNVs is minor, CNV analysis can be used when there are no other genetic causes identified. Causative CNVs are less common in SRNS than in other monogenic kidney diseases, such as congenital anomalies of the kidneys and urinary tract, where the detection rate was 5.3%.

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Data availability

Depersonalized data that this study is based on are available from the corresponding author upon request.

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Acknowledgements

We thank all participating families and physicians for their contribution. F.H. is the William E. Harmon Professor of Pediatrics at Harvard Medical School.

Funding

This research was supported by grants from the Department of Defense to S.S-C. (PR190746 and PR212415), and by grants from the National Institutes of Health to F.H. and S.S-C. (5RC-2DK122397-02), to F.H. (5R01-DK076683-16), and to N.D.M (T5T32-DK007726-37).

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Authors and Affiliations

  1. Division of Nephrology, Department of Medicine, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA

    Dalia Pantel, Nils D. Mertens, Ronen Schneider, Selina Hölzel, Shirlee Shril & Friedhelm Hildebrandt

  2. Institute of Human Genetics, Heidelberg University, Heidelberg, Germany

    Dalia Pantel

  3. Department of Pediatrics, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia

    Jameela A. Kari, Sherif El Desoky & Mohamed A. Shalaby

  4. Pediatric Nephrology Center of Excellence, King Abdulaziz University Hospital, Jeddah, Saudi Arabia

    Jameela A. Kari, Sherif El Desoky & Mohamed A. Shalaby

  5. Division of Nephrology, Department of Medicine, Columbia University, New York, NY, USA

    Tze Y. Lim & Simone Sanna-Cherchi

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  1. Dalia Pantel
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Contributions

Conceptualization: D.P., F.H., S.S.; Data Curation: D.P., S.S., T.Y.L.; Analysis and interpretation of data: D.P., N.D.M, R.S., S.H., S.S., T.Y.L.; Funding Acquisition: F.H., S.S-C.; Methodology: S.S-C., S.S., T.Y.L.; Project Administration: F.H.; Acquisition of Data: J.A.K., M.A.S., S.E.D.; Software: S.S., T.Y.L.; Supervision: F.H.; Validation: D.P., S.S.; Visualization: D.P.; Writing-original draft: D.P., F.H.; Writing-review and editing: F.H., N.D.M., S.S-C., S.S., T.Y.L.

Corresponding author

Correspondence to Friedhelm Hildebrandt.

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Ethics approval and consent

This study was approved by the institutional review board of Boston Children’s Hospital as well as institutional review boards of institutions where families were recruited. Before inclusion, written informed consent of each individual or their legal guardians was obtained.

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The authors have no competing interests to declare that are relevant to the content of this article.

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Pantel, D., Mertens, N.D., Schneider, R. et al. Copy number variation analysis in 138 families with steroid-resistant nephrotic syndrome identifies causal homozygous deletions in PLCE1 and NPHS2 in two families. Pediatr Nephrol 39, 455–461 (2024). https://doi.org/10.1007/s00467-023-06134-2

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