Genomic Testing in Patients with Kidney Failure of an Unknown Cause: a National Australian Study-Reference-Cited by-同舟云学术

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

Published:2024-05-03 Issue: Volume: Page:
ISSN:1555-9041
Container-title:Clinical Journal of the American Society of Nephrology
language:en
Short-container-title:CJASN

Author:

Mallawaarachchi Amali C.¹²³^ORCID,Fowles Lindsay⁴^ORCID,Wardrop Louise⁵^ORCID,Wood Alasdair⁵,O’Shea Rosie³^ORCID,Biros Erik³⁶⁷^ORCID,Harris Trudie³⁷^ORCID,Alexander Stephen I⁸⁹¹⁰,Bodek Simon¹¹^ORCID,Boudville Neil¹²^ORCID,Burke Jo¹³¹⁴,Burnett Leslie²¹⁵¹⁶^ORCID,Casauria Sarah¹⁷^ORCID,Chadban Steve¹⁸^ORCID,Chakera Aron¹⁹²⁰^ORCID,Crafter Sam²¹,Dai Pei²²²³^ORCID,De Fazio Paul²⁴,Faull Randall²⁵²⁶,Honda Andrew²⁷^ORCID,Huntley Vanessa²⁸^ORCID,Jahan Sadia²⁹^ORCID,Jayasinghe Kushani³⁰³¹³²^ORCID,Jose Matthew³³^ORCID,Leaver Anna¹¹^ORCID,MacShane Mandi³⁴³⁵,Madelli Evanthia Olympia¹⁷^ORCID,Nicholls Kathy³⁶³⁷^ORCID,Pawlowski Rhonda³⁸,Rangan Gopi³⁹⁴⁰^ORCID,Snelling Paul¹⁸^ORCID,Soraru Jacqueline⁴¹⁴²^ORCID,Sundaram Madhivanan⁴³^ORCID,Tchan Michel⁴⁴⁴⁵^ORCID,Valente Giulia¹¹^ORCID,Wallis Mathew¹³¹⁴⁴⁶^ORCID,Wedd Laura⁴⁷,Welland Matthew⁴⁷⁴⁸^ORCID,Whitlam John⁴⁹^ORCID,Wilkins Ella J²⁴^ORCID,McCarthy Hugh⁸¹⁰⁵⁰,Simons Cas⁴⁷⁴⁸⁵¹^ORCID,Quinlan Catherine⁵¹⁵²⁵³^ORCID,Patel Chirag⁴^ORCID,Stark Zornitza¹⁷²⁴⁵³^ORCID,Mallett Andrew³⁷¹⁷⁵⁴^ORCID

Affiliation:

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

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

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

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

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

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

7. Townsville University Hospital, Townsville, Queensland, Australia

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

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

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

11. Clinical Genetics Service, Austin Health, Melbourne, Australia

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

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

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

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

16. St Vincent's Healthcare Clinical Campus, UNSW Sydney

17. Australian Genomics, Murdoch Children’s Research Institute, Melbourne, Australia

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

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

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

21. The Women’s and Children’s Hospital, South Australia, Australia

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

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

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

25. Renal Unit, Royal Adelaide Hospital, SA, Australia

26. University of Adelaide, SA, Australia

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

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

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

30. Department of Medicine, Monash University, Melbourne, Australia

31. Department of Nephrology, Monash Health, Melbourne, Australia

32. Melbourne Health, Melbourne, Australia

33. Royal Hobart Hospital, Tasmania, Australia

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

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

36. Nephrology Unit Royal Melbourne Hospital Parkville Australia

37. The University of Melbourne Parkville, Australia

38. Anatomical Pathology, Monash Health, Melbourne, Australia

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

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

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

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

43. Royal Darwin Hospital, Northern Territory, Australia

44. Genetic Medicine, Westmead Hospital, Sydney NSW, Australia

45. Sydney Medical School, University of Sydney, Australia

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

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

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

49. Department of Nephrology, Austin Health, Melbourne, Australia

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

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

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

53. Department of Paediatrics, University of Melbourne, Australia

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

Abstract

Background 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. Methods 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. Results 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. Conclusions In this prospectively ascertained Australian cohort, we identified a genetic diagnosis in 25% of patients with kidney failure of unknown cause.

Funder

National Health and Medical Research Council

Publisher

Ovid Technologies (Wolters Kluwer Health)

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