Enhancing diagnostic outcomes in kidney genetic disorders: the KidGen national kidney genomics study protocol

Amali Mallawaarachchi^{1

2

3}, Hugh McCarthy^{4

5

6

7}, Thomas A Forbes^{1

8

9

10}, Kushani Jayasinghe^{1

11

12

13}, Chirag Patel^{1

14}, Stephen I Alexander^{5

7}, Tiffany Boughtwood^{13

15}, Jeffrey Braithwaite¹⁶, Aron Chakera¹⁷, Sam Crafter¹⁸, Ira W Deveson², Randall Faull¹⁹, Trudie Harris^{13

20}, Lilian Johnstone^{21

22}, Matthew Jose²³, Anna Leaver²⁴, Melissa H Little¹³, Daniel MacArthur^{25

26}, Tessa Mattiske^{13

15}, Christine Mincham²⁷, Kathy Nicholls²⁸, Catherine Quinlan^{1

9

10

29

30}, Michael C J Quinn^{14

15}, Gopala Rangan^{31

32}, Jessica Ryan³³, Cas Simons^{25

34}, Ian Smyth³⁵, Madhivanan Sundaram³⁶, Peter Trnka³⁷, Laura Wedd², Erik Biros^{13

20

38}, Zornitza Stark^{1

27

39}, Andrew Mallett^{40

41

42

43

44}

Affiliations

¹ The KidGen Collaborative, Australian Genomics, Melbourne, VIC, Australia.
² Garvan Institute of Medical Research, Sydney, NSW, Australia.
³ Clinical Genetics Service, Institute of Precision Medicine and Bioinformatics, Royal Prince Alfred Hospital, New South Wales, Australia.
⁴ School of Medicine, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
⁵ Centre for Kidney Research, The Children's Hospital at Westmead, Sydney, NSW, Australia.
⁶ Department of Nephrology, The Children's Hospital at Westmead, Sydney, NSW, Australia.
⁷ Department of Nephrology, Sydney Children's Hospital, Sydney, NSW, Australia.
⁸ Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.
⁹ Department of Nephrology, Royal Children's Hospital, Melbourne, VIC, Australia.
¹⁰ Kidney Regeneration, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
¹¹ Department of Nephrology, Monash Medical Centre, Melbourne, VIC, Australia.
¹² School of Clinical Sciences, Monash University, Melbourne, VIC, Australia.
¹³ Murdoch Children's Research Institute, Melbourne, VIC, Australia.
¹⁴ Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
¹⁵ Australian Genomics, Melbourne, VIC, Australia.
¹⁶ Centre for Healthcare Resilience and Implementation Science, Australian Institute of Health Innovation, Macquarie University, New South Wales, Australia.
¹⁷ Sir Charles Gairdner Hospital, Perth, WA, Australia.
¹⁸ Women's and Children's Hospital, Adelaide, South Australia, Australia.
¹⁹ Royal Adelaide Hospital, Adelaide, South Australia, Australia.
²⁰ Townsville University Hospital, Townsville, QLD, Australia.
²¹ Department of Nephrology, Monash Children's Hospital, Monash Health, Melbourne, VIC, Australia.
²² Department of Paediatrics, Monash University, Melbourne, VIC, Australia.
²³ Royal Hobart Hospital, Hobart, TAS, Australia.
²⁴ Austin Hospital, Melbourne, VIC, Australia.
²⁵ Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
²⁶ Centre for Population Genomics, Garvan Institute of Medical Research, University of New South Wales, Sydney, NSW, Australia.
²⁷ Perth 's Hospital, Perth, WA, Australia.
²⁸ Royal Melbourne Hospital, Melbourne, VIC, Australia.
²⁹ Department of Paediatrics, The University of Melbourne, Melbourne, VIC, Australia.
³⁰ Melbourne Genomics Health Alliance, Melbourne, VIC, Australia.
³¹ Department of Renal Medicine, Westmead Hospital, Sydney, NSW, Australia.
³² Michael Stern Laboratory for PKD, Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia.
³³ Monash Health, Melbourne, VIC, Australia.
³⁴ Centre for Population Genomics, Garvan Institute of Medical Research, Sydney, NSW, Australia.
³⁵ Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia.
³⁶ Royal Darwin Hospital, Darwin, NT, Australia.
³⁷ Queensland 's Hospital, Brisbane, QLD, Australia.
³⁸ College of Medicine and Dentistry, James Cook University, Townsville, QLD, Australia.
³⁹ Victorian Clinical Genetics Services, Melbourne, VIC, Australia.
⁴⁰ The KidGen Collaborative, Australian Genomics, Melbourne, VIC, Australia. andrew.mallett@health.qld.gov.au.
⁴¹ Murdoch Children's Research Institute, Melbourne, VIC, Australia. andrew.mallett@health.qld.gov.au.
⁴² Townsville University Hospital, Townsville, QLD, Australia. andrew.mallett@health.qld.gov.au.
⁴³ College of Medicine and Dentistry, James Cook University, Townsville, QLD, Australia. andrew.mallett@health.qld.gov.au.
⁴⁴ Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia. andrew.mallett@health.qld.gov.au.

PMID: 39901087
PMCID: PMC11792728
DOI: 10.1186/s12882-024-03926-y

Enhancing diagnostic outcomes in kidney genetic disorders: the KidGen national kidney genomics study protocol

Amali Mallawaarachchi et al. BMC Nephrol. 2025.

. 2025 Feb 3;26(1):51.

doi: 10.1186/s12882-024-03926-y.

Authors

Affiliations

¹ The KidGen Collaborative, Australian Genomics, Melbourne, VIC, Australia.
² Garvan Institute of Medical Research, Sydney, NSW, Australia.
³ Clinical Genetics Service, Institute of Precision Medicine and Bioinformatics, Royal Prince Alfred Hospital, New South Wales, Australia.
⁴ School of Medicine, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
⁵ Centre for Kidney Research, The Children's Hospital at Westmead, Sydney, NSW, Australia.
⁶ Department of Nephrology, The Children's Hospital at Westmead, Sydney, NSW, Australia.
⁷ Department of Nephrology, Sydney Children's Hospital, Sydney, NSW, Australia.
⁸ Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.
⁹ Department of Nephrology, Royal Children's Hospital, Melbourne, VIC, Australia.
¹⁰ Kidney Regeneration, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
¹¹ Department of Nephrology, Monash Medical Centre, Melbourne, VIC, Australia.
¹² School of Clinical Sciences, Monash University, Melbourne, VIC, Australia.
¹³ Murdoch Children's Research Institute, Melbourne, VIC, Australia.
¹⁴ Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
¹⁵ Australian Genomics, Melbourne, VIC, Australia.
¹⁶ Centre for Healthcare Resilience and Implementation Science, Australian Institute of Health Innovation, Macquarie University, New South Wales, Australia.
¹⁷ Sir Charles Gairdner Hospital, Perth, WA, Australia.
¹⁸ Women's and Children's Hospital, Adelaide, South Australia, Australia.
¹⁹ Royal Adelaide Hospital, Adelaide, South Australia, Australia.
²⁰ Townsville University Hospital, Townsville, QLD, Australia.
²¹ Department of Nephrology, Monash Children's Hospital, Monash Health, Melbourne, VIC, Australia.
²² Department of Paediatrics, Monash University, Melbourne, VIC, Australia.
²³ Royal Hobart Hospital, Hobart, TAS, Australia.
²⁴ Austin Hospital, Melbourne, VIC, Australia.
²⁵ Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
²⁶ Centre for Population Genomics, Garvan Institute of Medical Research, University of New South Wales, Sydney, NSW, Australia.
²⁷ Perth 's Hospital, Perth, WA, Australia.
²⁸ Royal Melbourne Hospital, Melbourne, VIC, Australia.
²⁹ Department of Paediatrics, The University of Melbourne, Melbourne, VIC, Australia.
³⁰ Melbourne Genomics Health Alliance, Melbourne, VIC, Australia.
³¹ Department of Renal Medicine, Westmead Hospital, Sydney, NSW, Australia.
³² Michael Stern Laboratory for PKD, Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia.
³³ Monash Health, Melbourne, VIC, Australia.
³⁴ Centre for Population Genomics, Garvan Institute of Medical Research, Sydney, NSW, Australia.
³⁵ Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia.
³⁶ Royal Darwin Hospital, Darwin, NT, Australia.
³⁷ Queensland 's Hospital, Brisbane, QLD, Australia.
³⁸ College of Medicine and Dentistry, James Cook University, Townsville, QLD, Australia.
³⁹ Victorian Clinical Genetics Services, Melbourne, VIC, Australia.
⁴⁰ The KidGen Collaborative, Australian Genomics, Melbourne, VIC, Australia. andrew.mallett@health.qld.gov.au.
⁴¹ Murdoch Children's Research Institute, Melbourne, VIC, Australia. andrew.mallett@health.qld.gov.au.
⁴² Townsville University Hospital, Townsville, QLD, Australia. andrew.mallett@health.qld.gov.au.
⁴³ College of Medicine and Dentistry, James Cook University, Townsville, QLD, Australia. andrew.mallett@health.qld.gov.au.
⁴⁴ Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia. andrew.mallett@health.qld.gov.au.

PMID: 39901087
PMCID: PMC11792728
DOI: 10.1186/s12882-024-03926-y

Abstract

Background: Genetic kidney disease (GKD) significantly affects the community and is responsible for a notable portion of adult kidney disease cases and about half of cases in paediatric patients. It substantially impacts the quality of life and life expectancy for affected children and adults across all stages of kidney disease. Precise genetic diagnosis in GKD promises to improve patient outcomes, provide access to targeted treatments, and reduce the disease burden for individuals, families, and healthcare systems. Genetic investigations are increasingly used in nephrology practice; however, many patients who undergo testing still lack a definitive diagnosis.

Methods: The KidGen National Kidney Genomics Study aims to increase diagnostic yield for those with suspected monogenic kidney disease without a diagnosis after standard diagnostic genetic testing. The program will seek to enrol up to 200 families from KidGen Collaborative kidney genetics clinics across Australia who have yet to receive conclusive diagnoses despite prior testing. Participants will undergo a personalised pathway of research genomic investigations. These include re-analysing existing data and/or undergoing advanced genomic testing methods, including short and long-read whole-genome sequencing, RNA sequencing, and functional genomics strategies using mouse modelling or kidney organoids.

Discussion: The KidGen National Kidney Genomics Study is a coordinated, multidisciplinary extension of previous research projects that aims to assess the diagnostic yield of advanced genomic approaches. The study's evidence will drive changes to current diagnostic pathways, including identifying which chronic kidney disease patients are most likely to benefit from a more comprehensive genomic approach to diagnosis.

Keywords: Advanced genomic testing; Diagnostic yield; Genetic kidney disease; Re-analysis; Study protocol; Undiagnosed patients.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: This project will be conducted according to the ethical principles outlined in the Declaration of Helsinki. The Human Research Ethics Committee (HREC) at the Royal Children’s Hospital in Melbourne, Australia (HREC/83945/RCHM-2022) has granted ethical approval in addition to existing ethics approval under Australian Genomics (HREC/16/MH/251). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

Figures

**Fig. 1**
KidGen national kidney genomics program: improving diagnostic outcomes for Australian families with genetic kidney disease. The KidGen network is a nationwide initiative led by the national multidisciplinary team (nMDT), coordinating kidney genetic clinics (KGCs) across Australia. This collaborative framework offers subsidised clinical gene panels to streamline diagnostic genomics. While achieving considerable success with a diagnostic yield slightly below 50%, an inventive proposal has emerged. The aim is to expand genetic testing boundaries by improving.ariant identification and classification and synergistically integrating genomic technologies with clinical expertise. This ambitious approach aims to enhance genetic diagnosis standards and improve the application of clinical best practices, representing a significant step forward in comprehensive patient renal care

**Fig. 2**
Australia's renal genetic services: a geographic breakdown. The KidGen Collaborative includes a network of 19 adult (green pins) and pediatric (blue pins) kidney genetics clinics (KGCs) operating nationwide. KGCs receive diagnostic support from the National Association of Testing Authorities (NATA)-accredited labs (orange pins), while research groups (purple pins) conduct functional genomics activities and perform subsequent variant curation in the background. NT, Northern Territory; QLD, Queensland; NSW, New South Wales; ACT, Australian Capital Territory; VIC, Victoria; TAS, Tasmania; SA, South Australia; WA, Western Australia

**Fig. 3**
KidGen research pathway for genomic testing. The foundation of KidGen’s genomic research is short-read whole genome sequencing (WGS) combined with advanced genomic analysis, a proven method for increasing diagnostic success. The process further involves in-depth genomic testing that prioritises variants based on patient traits and uses various advanced analysis methods, including functional genomics and long-read sequencing, and potentially integrates the results with gene expression data obtained from human urine-derived renal epithelial cells (HURECs). This process aims to provide information for diagnosis and potential discussions at a national multidisciplinary team (MDT) meeting to generate clinically reportable outcomes

**Fig. 4**
Mouse vs. organoid models: decoding kidney disease genetics. Mouse models and organoids serve as complementary tools in disease research, each offering distinct advantages. Mice are particularly well-suited for studying diseases caused by a small number of genes (candidate oligogenic genotypes), diseases affecting organs other than the kidneys (extra-renal phenotypes), and diseases with a later onset in life (adult-onset). Conversely, organoids excel in modelling diseases with early onset in life (antenatal/perinatal onset). They are valuable for developing personalised therapies because they can be cultured from a patient's cells

See this image and copyright information in PMC

References

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Enhancing diagnostic outcomes in kidney genetic disorders: the KidGen national kidney genomics study protocol

Affiliations

Enhancing diagnostic outcomes in kidney genetic disorders: the KidGen national kidney genomics study protocol

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

LinkOut - more resources

Full Text Sources