Mallawaarachchi, Amali C

Fowles, Lindsay

Wardrop, Louise

Wood, Alasdair

O'Shea, Rosie

Biros, Erik

Harris, Trudie

Alexander, Stephen I

Bodek, Simon

Boudville, Neil

Burke, Jo

Burnett, Leslie

Casauria, Sarah

Chadban, Steve

Chakera, Aron

Crafter, Sam

Dai, Pei

De Fazio, Paul

Faull, Randall

Honda, Andrew

Huntley, Vanessa

Jahan, Sadia

Jayasinghe, Kushani

Jose, Matthew

Leaver, Anna

MacShane, Mandi

Madelli, Evanthia Olympia

Nicholls, Kathy

Pawlowski, Rhonda

Rangan, Gopi

Snelling, Paul

Soraru, Jacqueline

Sundaram, Madhivanan

Tchan, Michel

Valente, Giulia

Wallis, Mathew

Wedd, Laura

Welland, Matthew

Whitlam, John

Wilkins, Ella J

McCarthy, Hugh

Simons, Cas

Quinlan, Catherine

Patel, Chirag

Stark, Zornitza

Mallett, Andrew

2024-05-03

The cause of kidney failure is unknown in approximately 10% of patients with stage 5 chronic kidney disease (CKD). For those who first present to nephrology care with kidney failure, standard investigations of serology, imaging, urinalysis and kidney biopsy are limited differentiators of etiology. We aimed to determine the diagnostic utility of whole-genome sequencing (WGS) with analysis of a broad kidney gene panel in patients with kidney failure of unknown cause.We prospectively recruited 100 participants who reached CKD stage 5 at 50 years of age and had an unknown cause of kidney failure after standard investigation. Clinically-accredited WGS was performed in this national cohort after genetic counselling. The primary analysis was targeted to 388 kidney-related genes with second-tier genome-wide and mitochondrial analysis.The cohort was 61% male and the average age of participants at stage 5 CKD was 32 years (9 months to 50 years). A genetic diagnosis was made in 25% of participants. Disease-causing variants were identified across autosomal dominant tubulointerstitial kidney disease (6), glomerular disorders (4), ciliopathies (3), tubular disorders (2), Alport syndrome (4) and mitochondrial disease (1). Most diagnoses (80%) were in autosomal dominant, X-linked or mitochondrial conditions (UMOD; COL4A5; INF2; CLCN5; TRPC6; COL4A4; EYA1; HNF1B; WT1; NBEA; m.3243A>G). Patients with a family history of CKD were more likely to have a positive result (OR 3.29, 95% CI 1.10-11.29). Thirteen percent of participants without a CKD family history had a positive result. In those who first presented in stage 5 CKD, WGS with broad analysis of a curated kidney-disease gene panel was diagnostically more informative than kidney biopsy, with biopsy being inconclusive in 24 of 25 participants.In this prospectively ascertained Australian cohort, we identified a genetic diagnosis in 25% of patients with kidney failure of unknown cause.

Clinical Genetics Service, Institute of Precision Medicine and Bioinformatics, Royal Prince Alfred Hospital, Sydney, Australia.

Genomic and Inherited Diseases Program, Garvan Institute of Medical Research, Sydney, Australia.

KidGen Collaborative, Australian Genomics Health Alliance, Murdoch Children's Research Institute, Melbourne, Australia.

Genetic Health Queensland, Royal Brisbane and Women's Hospital, Herston QLD, Australia.

KidGen Collaborative, Kidney Regeneration, Murdoch Children's Research Institute.

KidGen Collaborative, Kidney Regeneration, Murdoch Children's Research Institute.

KidGen Collaborative, Australian Genomics Health Alliance, Murdoch Children's Research Institute, Melbourne, Australia.

KidGen Collaborative, Australian Genomics Health Alliance, Murdoch Children's Research Institute, Melbourne, Australia.

College of Medicine & Dentistry, James Cook University, Townsville, Queensland, Australia.

Townsville University Hospital, Townsville, Queensland, Australia.

KidGen Collaborative, Australian Genomics Health Alliance, Murdoch Children's Research Institute, Melbourne, Australia.

Townsville University Hospital, Townsville, Queensland, Australia.

Centre for Kidney Research at the Children's Hospital at Westmead, NSW, Australia.

Department of Nephrology, Children's Hospital at Westmead, Sydney, Australia.

Discipline of Child and Adolescent Health, Faculty of Medicine and Health, University of Sydney, NSW, Australia.

Clinical Genetics Service, Austin Health, Melbourne, Australia.

Medical School, University of Western Australia, WA, Australia.

School of Medicine and Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.

Tasmanian Clinical Genetics Service, Royal Hobart Hospital, Tasmania, Australia.

Genomic and Inherited Diseases Program, Garvan Institute of Medical Research, Sydney, Australia.

Northern Clinical School, Faculty of Medicine and Health, University of Sydney.

St Vincent's Healthcare Clinical Campus, UNSW Sydney.

Australian Genomics, Murdoch Children's Research Institute, Melbourne, Australia.

Renal Medicine, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.

Harry Perkins Institute for Medical Research, University of Western Australia and UWA.

Renal Unit, Sir Charles Gairdner Hospital, Nedlands 6009, Western Australia.

The Women's and Children's Hospital, South Australia, Australia.

Precision Immunology Program, Garvan Institute of Medical Research, Sydney, Australia.

St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, Australia.

Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia.

Renal Unit, Royal Adelaide Hospital, SA, Australia.

University of Adelaide, SA, Australia.

The Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, Australia.

Adult Genetics Service, Royal Adelaide Hospital, SA, Australia.

The Central and Northern Renal and Transplantation Service, Royal Adelaide Hospital, Adelaide, Australia.

Department of Medicine, Monash University, Melbourne, Australia.

Department of Nephrology, Monash Health, Melbourne, Australia.

Melbourne Health, Melbourne, Australia.

Royal Hobart Hospital, Tasmania, Australia.

Clinical Genetics Service, Austin Health, Melbourne, Australia.

Genetic Services of WA, KEMH, Subiaco WA, Australia.

Harry Perkins Institute of Medical Research, Nedlands WA, Australia.

Australian Genomics, Murdoch Children's Research Institute, Melbourne, Australia.

Nephrology Unit Royal Melbourne Hospital Parkville Australia.

The University of Melbourne Parkville, Australia.

Anatomical Pathology, Monash Health, Melbourne, Australia.

Department of Renal Medicine, Westmead Hospital, Western Sydney Local Health District, Australia.

Michael Stern Laboratory for Polycystic Kidney Disease, Westmead Institute for Medical Research, Australia.

Renal Medicine, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.

Department of Nephrology and Hypertension, Perth Children's Hospital, Perth, Australia.

Department of Nephrology and Renal Transplantation, Fiona Stanley Hospital, Perth, Australia.

Royal Darwin Hospital, Northern Territory, Australia.

Genetic Medicine, Westmead Hospital, Sydney NSW, Australia.

Sydney Medical School, University of Sydney, Australia.

Clinical Genetics Service, Austin Health, Melbourne, Australia.

School of Medicine and Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.

Tasmanian Clinical Genetics Service, Royal Hobart Hospital, Tasmania, Australia.

Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.

Centre for Population Genomics, Garvan Institute of Medical Research and UNSW Sydney, Sydney, Australia.

Centre for Population Genomics, Garvan Institute of Medical Research and UNSW Sydney, Sydney, Australia.

Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, Australia.

Department of Nephrology, Austin Health, Melbourne, Australia.

Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia.

Centre for Kidney Research at the Children's Hospital at Westmead, NSW, Australia.

Discipline of Child and Adolescent Health, Faculty of Medicine and Health, University of Sydney, NSW, Australia.

Department of Nephrology, Sydney Children's Hospitals Network, NSW, Australia.

Centre for Population Genomics, Garvan Institute of Medical Research and UNSW Sydney, Sydney, Australia.

Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, Australia.

Department of Kidney Regeneration, Murdoch Children's Research Institute, Melbourne, Australia.

Department of Kidney Regeneration, Murdoch Children's Research Institute, Melbourne, Australia.

Department of Nephrology, Royal Children's Hospital, Melbourne, Australia.

Department of Paediatrics, University of Melbourne, Australia.

Genetic Health Queensland, Royal Brisbane and Women's Hospital, Herston QLD, Australia.

Australian Genomics, Murdoch Children's Research Institute, Melbourne, Australia.

Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia.

Department of Paediatrics, University of Melbourne, Australia.

KidGen Collaborative, Australian Genomics Health Alliance, Murdoch Children's Research Institute, Melbourne, Australia.

Townsville University Hospital, Townsville, Queensland, Australia.

Australian Genomics, Murdoch Children's Research Institute, Melbourne, Australia.

Institute for Molecular Bioscience and Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.

Clin J Am Soc Nephrol . 2024 May 3. doi: 10.2215/CJN.0000000000000464. Online ahead of print.

1555-905X

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https://pubmed.ncbi.nlm.nih.gov/38861662/?otool=iaurydwlib

https://hdl.handle.net/10137/13406

Genomic Testing in Patients with Kidney Failure of an Unknown Cause: a National Australian Study.

Journal Article

Publication