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Isolated proteinuria due to CUBN homozygous mutation - challenging the investigative paradigm.
BMC Nephrol 2019; 20(1):330BN

Abstract

BACKGROUND

Proteinuria is a common clinical presentation, the diagnostic workup for which involves many non-invasive 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.

Authors+Show Affiliations

Department of Nephrology, Monash Medical Centre, Melbourne, Australia. Monash University, Melbourne, Australia. Murdoch Children's Research Institute, Melbourne, Australia. The KidGen Collaborative, Australian Genomics Health Alliance, Victoria, Australia.The KidGen Collaborative, Australian Genomics Health Alliance, Victoria, Australia. Department of Paediatrics, University of Melbourne, Victoria, Australia. Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia.Department of Nephrology, Monash Medical Centre, Melbourne, Australia. Monash University, Melbourne, Australia.Department of Pathology, Royal Children's Hospital, Melbourne, Australia.Murdoch Children's Research Institute, Melbourne, Australia. The KidGen Collaborative, Australian Genomics Health Alliance, Victoria, Australia. Department of Paediatrics, University of Melbourne, Victoria, Australia. Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia.Murdoch Children's Research Institute, Melbourne, Australia. The KidGen Collaborative, Australian Genomics Health Alliance, Victoria, Australia. Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia.Murdoch Children's Research Institute, Melbourne, Australia. The KidGen Collaborative, Australian Genomics Health Alliance, Victoria, Australia.Murdoch Children's Research Institute, Melbourne, Australia. The KidGen Collaborative, Australian Genomics Health Alliance, Victoria, Australia. Kidney Health Service and Conjoint Renal Research Laboratory, Royal Brisbane and Women's Hospital, Brisbane, Australia. Institute for Molecular Bioscience and Faculty of Medicine, The University of Queensland, Brisbane, Australia.Murdoch Children's Research Institute, Melbourne, Australia. catherine.quinlan@rch.org.au. The KidGen Collaborative, Australian Genomics Health Alliance, Victoria, Australia. catherine.quinlan@rch.org.au. Department of Paediatric Nephrology, Royal Children's Hospital, 50 Flemington Street, Parkville, Australia. catherine.quinlan@rch.org.au.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31438875

Citation

Jayasinghe, Kushani, et al. "Isolated Proteinuria Due to CUBN Homozygous Mutation - Challenging the Investigative Paradigm." BMC Nephrology, vol. 20, no. 1, 2019, p. 330.
Jayasinghe K, White SM, Kerr PG, et al. Isolated proteinuria due to CUBN homozygous mutation - challenging the investigative paradigm. BMC Nephrol. 2019;20(1):330.
Jayasinghe, K., White, S. M., Kerr, P. G., MacGregor, D., Stark, Z., Wilkins, E., ... Quinlan, C. (2019). Isolated proteinuria due to CUBN homozygous mutation - challenging the investigative paradigm. BMC Nephrology, 20(1), p. 330. doi:10.1186/s12882-019-1474-z.
Jayasinghe K, et al. Isolated Proteinuria Due to CUBN Homozygous Mutation - Challenging the Investigative Paradigm. BMC Nephrol. 2019 Aug 22;20(1):330. PubMed PMID: 31438875.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Isolated proteinuria due to CUBN homozygous mutation - challenging the investigative paradigm. AU - Jayasinghe,Kushani, AU - White,Susan M, AU - Kerr,Peter G, AU - MacGregor,Duncan, AU - Stark,Zornitza, AU - Wilkins,Ella, AU - Simons,Cas, AU - Mallett,Andrew, AU - Quinlan,Catherine, Y1 - 2019/08/22/ PY - 2019/05/12/received PY - 2019/07/19/accepted PY - 2019/8/24/entrez PY - 2019/8/24/pubmed PY - 2019/8/24/medline KW - Chronic kidney disease KW - Genetics KW - Genomics SP - 330 EP - 330 JF - BMC nephrology JO - BMC Nephrol VL - 20 IS - 1 N2 - BACKGROUND: Proteinuria is a common clinical presentation, the diagnostic workup for which involves many non-invasive 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. SN - 1471-2369 UR - https://www.unboundmedicine.com/medline/citation/31438875/Isolated_proteinuria_due_to_CUBN_homozygous_mutation_-_challenging_the_investigative_paradigm L2 - https://www.biomedcentral.com/1471-2369/20/330 DB - PRIME DP - Unbound Medicine ER -