K JAYASINGHE1,2,3, C QUINLAN2,4,5, C SIMONS2,7, S WHITE2,6, A MALLETT4,8
1Department of Nephrology, Monash Health, Melbourne, Australia, 2Murdoch Childrens Research Institute (MCRI), Melbourne, Australia, 3Monash University, Melbourne, Australia, 4KidGen Renal Genetics Flagship, Australian Genomic Health Alliance, Australia, 5Department of Paediatric Nephrology, Royal Children’s Hospital, Melbourne, Australia, 6Department fo Paediatrics, Royal Children’s Hospital, Melbourne, Australia, 7University of Queensland, Brisbane, Australia, 8Genetic Health Queensland, Royal Brisbane and Women’s Hospital, Brisbane, Australia
Background: Proteinuria is a common kidney presentation. Historically, diagnostic workup of patients with isolated proteinuria involved thorough urinalysis, imaging and blood sampling before potentially proceeding to renal biopsy. However recent advances have resulted in reduced cost and increased availability of genomic sequencing for establishing clinical diagnoses.
Case Report: An 8 year old boy was referred with an incidental finding of persistent proteinuria during investigation for nonspecific abdominal pain. He had no haematuria and had normal serum albumin. All other investigations including blood analysis for haematological, biochemical and immunology parameters, renal ultrasound, ophthalmology and audiology assessment were unremarkable. Further assessment revealed consanguineous family history and a brother also with isolated proteinuria. Renal biopsy demonstrated normal light microscopy and global uniform thinning of the glomerular basement membrane 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 using the Genomic Oligoarray and single nucleotide polymorphism (SNP) Evaluation tool. Examination of these regions implicated CUBN, on chromosome 10p12.31. Research whole genome sequencing of both affected individuals was performed after informed consent (HREC/15/QRCH/126). This revealed a homozygous stop-gained variant in CUBN (NM_001081.3, c.4689_4690delTAinsAT, p.(CysIle1263*), ACMG Class 5).
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. Therefore, we describe how genomics can successfully identify single gene causes of nephropathy. This presents a case for genomic sequencing to be undertaken earlier in the diagnostic workup to reduce the need for invasive investigations, challenging the current diagnostic paradigm.
Dr Cathy Quinlan is a Paediatric Nephrologist in The Royal Children’s Hospital and Honorary Research Fellow at the Murdoch Childrens Research Institute. A graduate of University College Dublin, she completed her clinical training in the Children’s University Hospital in Dublin and Great Ormond Street Hospital in London. She completed research towards an MSc in Medical Education in Queens University Belfast and MD(Res) in University College London investigating the cardiovascular phenotype in juvenile-onset lupus before moving to the Melbourne Children’s Campus in 2013. Her research interests include inherited kidney disease, nephrotic syndrome, cystic fibrosis renal disease and peritoneal dialysis