nach oben

Erschienen in:

05.09.2023 | Original Article

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

verfasst von: Dalia Pantel, Nils D. Mertens, Ronen Schneider, Selina Hölzel, Jameela A. Kari, Sherif El Desoky, Mohamed A. Shalaby, Tze Y. Lim, Simone Sanna-Cherchi, Shirlee Shril, Friedhelm Hildebrandt

Erschienen in: Pediatric Nephrology | Ausgabe 2/2024

Einloggen, um Zugang zu erhalten

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%.

Graphical abstract

Nur mit Berechtigung zugänglich

Barnett HL, Edelmann CM, Greifer I (1981) Primary nephrotic syndrome in children: Clinical significance of histopathologic variants of minimal change and of diffuse mesangial hypercellularity. A report of the international study of kidney disease in children. Kidney Int 20:765–771. https://doi.org/10.1038/ki.1981.209CrossRef

Leonard MB, Donaldson LA, Ho M, Geary DF (2003) A prospective cohort study of incident maintenance dialysis in children: an NAPRTC study. Kidney Int 63:744–755. https://doi.org/10.1046/j.1523-1755.2003.00788.xCrossRefPubMed

Connaughton DM, Kennedy C, Shril S et al (2019) Monogenic causes of chronic kidney disease in adults. Kidney Int 95:914–928. https://doi.org/10.1016/j.kint.2018.10.031CrossRefPubMedPubMedCentral

Wiggins RC (2007) The spectrum of podocytopathies: A unifying view of glomerular diseases. Kidney Int 71:1205–1214CrossRefPubMed

Warejko JK, Tan W, Daga A et al (2018) Whole exome sequencing of patients with steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 13:53–62. https://doi.org/10.2215/CJN.04120417CrossRefPubMed

Sadowski CE, Lovric S, Ashraf S et al (2015) A Single-Gene Cause in 29.5% of Cases of Steroid-Resistant Nephrotic Syndrome. J Am Soc Nephrol 26:1279–1289. https://doi.org/10.1681/ASN.2014050489CrossRefPubMed

Mann N, Braun DA, Amann K et al (2019) Whole-Exome sequencing enables a precision medicine approach for kidney transplant recipients. J Am Soc Nephrol 30:201–215. https://doi.org/10.1681/ASN.2018060575CrossRefPubMedPubMedCentral

Zhao L, Liu H, Yuan X et al (2020) Comparative study of whole exome sequencing-based copy number variation detection tools. BMC Bioinformatics 21:97. https://doi.org/10.1186/s12859-020-3421-1CrossRefPubMedPubMedCentral

Krumm N, Sudmant PH, Ko A et al (2012) Copy number variation detection and genotyping from exome sequence data. Genome Res 22:1525–1532. https://doi.org/10.1101/gr.138115.112CrossRefPubMedPubMedCentral

10.

Klambauer G, Schwarzbauer K, Mayr A et al (2012) Cn.MOPS: Mixture of Poissons for discovering copy number variations in next-generation sequencing data with a low false discovery rate. Nucleic Acids Res 40:e69. https://doi.org/10.1093/nar/gks003CrossRefPubMedPubMedCentral

11.

Talevich E, Shain AH, Botton T, Bastian BC (2016) CNVkit: Genome-Wide Copy Number Detection and Visualization from Targeted DNA Sequencing. PLoS Comput Biol 12:e1004873. https://doi.org/10.1371/journal.pcbi.1004873CrossRefPubMedPubMedCentral

12.

Sathirapongsasuti JF, Lee H, Horst BAJ et al (2011) Exome sequencing-based copy-number variation and loss of heterozygosity detection: ExomeCNV. Bioinformatics 27:2648–2654. https://doi.org/10.1093/bioinformatics/btr462CrossRefPubMedPubMedCentral

13.

Tan R, Wang Y, Kleinstein SE et al (2014) An Evaluation of Copy Number Variation Detection Tools from Whole-Exome Sequencing Data. Hum Mutat 35:899–907. https://doi.org/10.1002/humu.22537CrossRefPubMed

14.

Wu C-HW, Lim TY, Wang C et al (2022) Copy Number Variation Analysis Facilitates Identification of Genetic Causation in Patients with Congenital Anomalies of the Kidney and Urinary Tract. Eur Urol Open Sci 44:106–112. https://doi.org/10.1016/J.EUROS.2022.08.004CrossRefPubMedPubMedCentral

15.

Sanna-Cherchi S, Kiryluk K, Burgess KE et al (2012) Copy-number disorders are a common cause of congenital kidney malformations. Am J Hum Genet 91:987–997. https://doi.org/10.1016/j.ajhg.2012.10.007CrossRefPubMedPubMedCentral

16.

Verbitsky M, Westland R, Perez A et al (2019) The copy number variation landscape of congenital anomalies of the kidney and urinary tract. Nat Genet 51:117–127. https://doi.org/10.1038/s41588-018-0281-yCrossRefPubMed

17.

Westland R, Verbitsky M, Vukojevic K et al (2015) Copy number variation analysis identifies novel CAKUT candidate genes in children with a solitary functioning kidney. Kidney Int 88:1402–1410. https://doi.org/10.1038/ki.2015.239CrossRefPubMedPubMedCentral

18.

Snoek R, van Setten J, Keating BJ et al (2018) NPHP1 (Nephrocystin-1) gene deletions cause adult-onset ESRD. J Am Soc Nephrol 29:1772–1779. https://doi.org/10.1681/ASN.2017111200CrossRefPubMedPubMedCentral

19.

Nakanishi K, Okamoto T, Nozu K et al (2019) Pair analysis and custom array CGH can detect a small copy number variation in COQ6 gene. Clin Exp Nephrol 23:669–675. https://doi.org/10.1007/s10157-018-1682-zCrossRefPubMed

20.

Nagano C, Nozu K, Morisada N et al (2018) Detection of copy number variations by pair analysis using next-generation sequencing data in inherited kidney diseases. Clin Exp Nephrol 22:881–888. https://doi.org/10.1007/s10157-018-1534-xCrossRefPubMed

21.

Gee HY, Otto EA, Hurd TW et al (2014) Whole-exome resequencing distinguishes cystic kidney diseases from phenocopies in renal ciliopathies. Kidney Int 85:880–887. https://doi.org/10.1038/ki.2013.450CrossRefPubMed

22.

Hermle T, Schneider R, Schapiro D et al (2018) GAPVD1 and ANKFY1 mutations implicate RAB5 regulation in nephrotic syndrome. J Am Soc Nephrol 29:2123–2138. https://doi.org/10.1681/ASN.2017121312CrossRefPubMedPubMedCentral

23.

Hinkes B, Wiggins RC, Gbadegesin R et al (2006) Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible. Nat Genet 38:1397–1405. https://doi.org/10.1038/ng1918CrossRefPubMed

24.

Boute N, Gribouval O, Roselli S et al (2000) NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat Genet 24:349–354. https://doi.org/10.1038/74166CrossRefPubMed

25.

Swaminathan GJ, Bragin E, Chatzimichali EA et al (2012) DECIPHER: web-based, community resource for clinical interpretation of rare variants in developmental disorders. Hum Mol Genet 21:R37–R44. https://doi.org/10.1093/hmg/dds362CrossRefPubMedPubMedCentral

26.

Firth HV, Richards SM, Bevan AP et al (2009) DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am J Hum Genet 84:524–533. https://doi.org/10.1016/j.ajhg.2009.03.010CrossRefPubMedPubMedCentral

27.

Miller DT, Adam MP, Aradhya S et al (2010) Consensus Statement: Chromosomal Microarray Is a First-Tier Clinical Diagnostic Test for Individuals with Developmental Disabilities or Congenital Anomalies. Am J Hum Genet 86:749–764. https://doi.org/10.1016/j.ajhg.2010.04.006CrossRefPubMedPubMedCentral

28.

Heeringa SF, Chernin G, Chaki M et al (2011) COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness. J Clin Invest 121:2013–2024. https://doi.org/10.1172/JCI45693CrossRefPubMedPubMedCentral

29.

Tan W, Lovric S, Ashraf S et al (2018) Analysis of 24 genes reveals a monogenic cause in 11.1% of cases with steroid-resistant nephrotic syndrome at a single center. Pediatr Nephrol 33:305–314. https://doi.org/10.1007/s00467-017-3801-6CrossRefPubMed

30.

Av D, Ghosh R, Yuan B et al (2019) Copy number variant and runs of homozygosity detection by microarrays enabled more precise molecular diagnoses in 11,020 clinical exome cases. Genome Med 11:30. https://doi.org/10.1186/s13073-019-0639-5CrossRef

31.

Boone PM, Campbell IM, Baggett BC et al (2013) Deletions of recessive disease genes: CNV contribution to carrier states and disease-causing alleles. Genome Res 23:1383–1394. https://doi.org/10.1101/gr.156075.113CrossRefPubMedPubMedCentral

32.

Lalani SR, Liu P, Rosenfeld JA et al (2016) Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-allelic TANGO2 Mutations. Am J Hum Genet 98:347–357. https://doi.org/10.1016/j.ajhg.2015.12.008CrossRefPubMedPubMedCentral

33.

ClinVar. National Center for Biotechnology Information, U.S. National Library of Medicine. Accessed July 1, 2023. http://www.ncbi.nlm.nih.gov/clinvar

34.

DECIPHER. Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Accessed July 1, 2023. https://decipher.sanger.ac.uk/

35.

ISCA. International Standards for Cytogenomic Arrays. Accessed July 1, 2023. https://www.clinicalgenome.org/

Titel: Copy number variation analysis in 138 families with steroid-resistant nephrotic syndrome identifies causal homozygous deletions in PLCE1 and NPHS2 in two families
verfasst von: Dalia Pantel
Nils D. Mertens
Ronen Schneider
Selina Hölzel
Jameela A. Kari
Sherif El Desoky
Mohamed A. Shalaby
Tze Y. Lim
Simone Sanna-Cherchi
Shirlee Shril
Friedhelm Hildebrandt
Publikationsdatum: 05.09.2023
Verlag: Springer Berlin Heidelberg
Erschienen in: Pediatric Nephrology / Ausgabe 2/2024
Print ISSN: 0931-041X
Elektronische ISSN: 1432-198X
DOI: https://doi.org/10.1007/s00467-023-06134-2

Update Pädiatrie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

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