Isolated proteinuria due to CUBN homozygous mutation – challenging the investigative paradigm

Jayasinghe, Kushani, White, Susan M., Kerr, Peter G., MacGregor, Duncan, Stark, Zornitza, Wilkins, Ella, Simons, Cas, Mallett, Andrew, and Quinlan, Catherine (2019) Isolated proteinuria due to CUBN homozygous mutation – challenging the investigative paradigm. BMC Nephrology, 20. 330.

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Background: Proteinuria is a common clinical presentation, the diagnostic workup for which involves many noninvasive and invasive investigations. We report on two siblings that highlight the clinically relevant functional role of cubulin for albumin resorption in the proximal tubule and supports the use of genomic sequencing early in the diagnostic work up of patients who present with proteinuria.

Case presentation: An 8-year-old boy was referred with an incidental finding of proteinuria. All preliminary investigations were unremarkable. Further assessment revealed consanguineous family history and a brother with isolated proteinuria. Renal biopsy demonstrated normal light microscopy and global glomerular basement membrane thinning on electron microscopy. Chromosomal microarray revealed long continuous stretches of homozygosity (LCSH) representing ~ 4.5% of the genome. Shared regions of LCSH between the brothers were identified and their further research genomic analysis implicated a homozygous stop-gain variant in CUBN (10p12.31).

Conclusions: CUBN mutations have been implicated as a hereditary cause of megaloblastic anaemia and variable proteinuria. This is the second reported family with isolated proteinuria due to biallelic CUBN variants in the absence of megaloblastic anaemia, demonstrating the ability of genomic testing to identify genetic causes of nephropathy within expanding associated phenotypic spectra. Genomic sequencing, undertaken earlier in the diagnostic trajectory, may reduce the need for invasive investigations and the time to definitive diagnosis for patients and families.

Item ID: 67870
Item Type: Article (Case Study)
ISSN: 1471-2369
Keywords: Genomics, Genetics, Chronic kidney disease
Copyright Information: © The Author(s). 2019Open Access. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver( applies to the data made available in this article, unless otherwise stated.
Funders: National Health and Medical Research Council of Australia (NHMRC)
Projects and Grants: NHMRC APP109865
Date Deposited: 21 Sep 2021 22:42
FoR Codes: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3202 Clinical sciences > 320213 Medical genetics (excl. cancer genetics) @ 80%
32 BIOMEDICAL AND CLINICAL SCIENCES > 3202 Clinical sciences > 320214 Nephrology and urology @ 20%
SEO Codes: 20 HEALTH > 2001 Clinical health > 200105 Treatment of human diseases and conditions @ 100%
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