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Whole exome sequencing identifies monogenic forms of nephritis in a previously unsolved cohort of children with steroid-resistant nephrotic syndrome and hematuria

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Abstract

Background

Alport syndrome (AS), atypical hemolytic-uremic syndrome (aHUS), and fibronectin-glomerulopathy (FG) are rare forms of glomerular diseases that manifest in a combination of proteinuria, hematuria, and hypertension, referred to as nephritic syndrome. Due to phenotypic overlays, steroid-resistant nephrotic syndrome (SRNS) and nephritic syndrome have been difficult to discern diagnostically. SRNS is more common than nephritic syndrome and is the second leading cause of childhood-onset CKD. Fourteen monogenic causes of AS, aHUS, and FG and 60 monogenic causes of SRNS have been identified. As whole exome sequencing (WES) allows for unequivocal molecular genetic diagnostics, we hypothesize to be able to identify causative mutations in genes known to cause nephritic syndrome in patient cohorts with a clinical diagnosis of SRNS.

Methods

We identified patients with hematuria and steroid-resistant proteinuria in an international patient cohort that we had submitted to WES and who were unsolved for known monogenic causes of SRNS. These 70 patients from 65 individual families were subsequently analyzed for causative mutations in 14 AS, aHUS, or FG causing genes. WES data were compared to a control cohort of 76 patients from 75 families that were diagnosed with nephronophthisis-related ciliopathies (NPHP-RC) and to a control cohort of 83 individuals from 75 families with SRNS, but without hematuria.

Results

We detected likely pathogenic genetic variants in 3 of 65 families (4.6%) in 2 of the 14 genes analyzed.

Conclusions

We confirmed that in cohorts of childhood-onset SRNS, patients with nephritic syndrome can be discerned by WES. The findings highlight the importance of clinical genetic testing for therapeutic and preventative measures in patients with proteinuria.

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Data availability

The data will be shared on reasonable request made to the corresponding author.

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Acknowledgements

We thank the participating families and the physicians for their contributions. F.H. is the William E. Harmon Professor of Pediatrics

Funding

This research was supported by grants from the National Institutes of Health (5R01DK076683-15 to FH).

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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

    Hongbo Xiao & Friedhelm Hildebrandt

  2. Division of Nephrology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China

    Hongbo Xiao

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  1. Hongbo Xiao
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  2. Friedhelm Hildebrandt
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Contributions

HX: analysis and interpretation of data, drafting of article; FH: conception and design of research work, drafting and revision of article.

Corresponding author

Correspondence to Friedhelm Hildebrandt.

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Ethics approval

This study was approved by the institutional review boards of Boston Children’s Hospital and the University of Michigan. DNA samples were collected between 09/1996 and 04/2016 for the nephritis cohort, and between 09/2017 and 08/2019 for the NPHP-RC cohort, after obtaining written informed consent, clinical data, and pedigree information (www.renalgenes.org).

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The authors declare no competing interests.

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Xiao, H., Hildebrandt, F. Whole exome sequencing identifies monogenic forms of nephritis in a previously unsolved cohort of children with steroid-resistant nephrotic syndrome and hematuria. Pediatr Nephrol 37, 1567–1574 (2022). https://doi.org/10.1007/s00467-021-05312-4

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  • DOI: https://doi.org/10.1007/s00467-021-05312-4

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