Genomic Testing in Patients with Kidney Failure of an Unknown Cause: A National Australian Study,Clinical Journal of the American Society of Nephrology

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Genomic Testing in Patients with Kidney Failure of an Unknown Cause: A National Australian Study
Clinical Journal of the American Society of Nephrology ( IF 8.5 ) Pub Date : 2024-05-03 , DOI: 10.2215/cjn.0000000000000464
Amali C Mallawaarachchi _{1,

2,

3} , Lindsay Fowles ₄ , Louise Wardrop ₅ , Alasdair Wood ₅ , Rosie O'Shea ₃ , Erik Biros _{3,

6,

7} , Trudie Harris _{3,

7} , Stephen I Alexander _{8,

9,

10} , Simon Bodek ₁₁ , Neil Boudville ₁₂ , Jo Burke _{13,

14} , Leslie Burnett _{2,

15,

16} , Sarah Casauria ₁₇ , Steve Chadban ₁₈ , Aron Chakera _{19,

20} , Sam Crafter ₂₁ , Pei Dai _{22,

23} , Paul De Fazio ₂₄ , Randall Faull _{25,

26} , Andrew Honda ₂₇ , Vanessa Huntley ₂₈ , Sadia Jahan ₂₉ , Kushani Jayasinghe _{30,

31,

32} , Matthew Jose ₃₃ , Anna Leaver ₁₁ , Mandi MacShane _{34,

35} , Evanthia Olympia Madelli ₁₇ , Kathy Nicholls _{36,

37} , Rhonda Pawlowski ₃₈ , Gopi Rangan _{39,

40} , Paul Snelling ₁₈ , Jacqueline Soraru _{41,

42} , Madhivanan Sundaram ₄₃ , Michel Tchan _{44,

45} , Giulia Valente ₁₁ , Mathew Wallis _{13,

14,

46} , Laura Wedd ₄₇ , Matthew Welland _{47,

48} , John Whitlam ₄₉ , Ella J Wilkins ₂₄ , Hugh McCarthy _{8,

10,

50} , Cas Simons _{47,

48,

51} , Catherine Quinlan _{51,

52,

53} , Chirag Patel ₄ , Zornitza Stark _{17,

24,

53} , Andrew J Mallett _{3,

7,

17,

54}

Affiliation

Clinical Genetics Service, Institute of Precision Medicine and Bioinformatics, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
Genomic and Inherited Diseases Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
KidGen Collaborative, Australian Genomics Health Alliance, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
Genetic Health Queensland, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia.
KidGen Collaborative, Kidney Regeneration, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
College of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia.
Townsville University Hospital, Townsville, Queensland, Australia.
Centre for Kidney Research at the Children's Hospital at Westmead, Sydney, New South Wales, Australia.
Department of Nephrology, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
Discipline of Child and Adolescent Health, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.
Clinical Genetics Service, Austin Health, Melbourne, Victoria, Australia.
Medical School, University of Western Australia, Crawley, Western Australia, Australia.
School of Medicine and Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
Tasmanian Clinical Genetics Service, Royal Hobart Hospital, Hobart, Tasmania, Australia.
Faculty of Medicine and Health, Northern Clinical School, University of Sydney, Sydney, New South Wales, Australia.
St Vincent's Healthcare Clinical Campus, UNSW Sydney, Sydney, New South Wales, Australia.
Australian Genomics, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
Renal Medicine, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
Harry Perkins Institute for Medical Research, University of Western Australia, Crawley, Western Australia, Australia.
Renal Unit, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
The Women's and Children's Hospital, North Adelaide, South Australia, Australia.
Precision Immunology Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
Faculty of Medicine, St Vincent's Clinical School, UNSW Sydney, Sydney, New South Wales, Australia.
Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
Renal Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
University of Adelaide, Adelaide, South Australia, Australia.
The Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
Adult Genetics Service, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
The Central and Northern Renal and Transplantation Service, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
Department of Medicine, Monash University, Melbourne, Victoria, Australia.
Department of Nephrology, Monash Health, Melbourne, Victoria, Australia.
Melbourne Health, Melbourne, Victoria, Australia.
Royal Hobart Hospital, Hobart, Tasmania, Australia.
Genetic Services of WA, KEMH, Subiaco, Western Australia, Australia.
Harry Perkins Institute of Medical Research, Nedlands, Western Australia, Australia.
Nephrology Unit, Royal Melbourne Hospital, Parkville, Victoria, Australia.
The University of Melbourne, Parkville, Victoria, Australia.
Anatomical Pathology, Monash Health, Melbourne, Victoria, Australia.
Department of Renal Medicine, Westmead Hospital, Western Sydney Local Health District, Sydney, New South Wales, Australia.
Michael Stern Laboratory for Polycystic Kidney Disease, Westmead Institute for Medical Research, Westmead, New South Wales, Australia.
Department of Nephrology and Hypertension, Perth Children's Hospital, Nedlands, Western Australia, Australia.
Department of Nephrology and Renal Transplantation, Fiona Stanley Hospital, Murdoch, Western Australia, Australia.
Royal Darwin Hospital, Tiwi, Northern Territory, Australia.
Genetic Medicine, Westmead Hospital, Sydney, New South Wales, Australia.
Sydney Medical School, University of Sydney, Sydney, New South Wales, 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, New South Wales, Australia.
Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
Department of Nephrology, Austin Health, Melbourne, Victoria, Australia.
Department of Nephrology, Sydney Children's Hospitals Network, Sydney, New South Wales, Australia.
Department of Kidney Regeneration, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
Department of Nephrology, Royal Children's Hospital, Melbourne, Victoria, Australia.
Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia.
Institute for Molecular Bioscience and Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.

age 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 the age of ≤50 years and had an unknown cause of kidney failure after standard investigation. Clinically accredited WGS was performed in this national cohort after genetic counseling. 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). Participants with a family history of CKD were more likely to have a positive result (odds ratio, 3.29; 95% confidence interval, 1.10 to 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 the 25 participants. Conclusions In this prospectively ascertained Australian cohort, we identified a genetic diagnosis in 25% of patients with kidney failure of unknown cause....

中文翻译：

不明原因肾衰竭患者的基因组检测：澳大利亚国家研究

5 岁慢性肾病 (CKD)。对于那些首次因肾衰竭而接受肾脏病治疗的患者来说，血清学、影像学、尿液分析和肾活检的标准检查是鉴别病因的有限手段。我们的目的是通过分析广泛的肾脏基因组来确定全基因组测序 (WGS) 对不明原因肾衰竭患者的诊断效用。方法我们前瞻性地招募了 100 名年龄≤50 岁达到 CKD 5 期且经标准调查后肾衰竭原因不明的参与者。在遗传咨询后，在这个国家队列中进行了临床认可的全基因组测序。主要分析针对 388 个肾脏相关基因，并进行二级全基因组分析和线粒体分析。结果该队列中 61% 为男性，5 期 CKD 参与者的平均年龄为 32 岁（9 个月至 50 岁）。 25% 的参与者进行了基因诊断。在常染色体显性肾小管间质性肾病 (6)、肾小球疾病 (4)、纤毛病 (3)、肾小管疾病 (2)、阿尔波特综合征 (4) 和线粒体疾病 (1) 中发现了致病变异。大多数诊断 (80%) 属于常染色体显性遗传、X 连锁或线粒体疾病 (UMOD; COL4A5; INF2; CLCN5; TRPC6; COL4A4; EYA1; HNF1B; WT1; NBEA; m.3243A>G)。有 CKD 家族史的参与者更有可能获得阳性结果（比值比，3.29；95% 置信区间，1.10 至 11.29）。没有 CKD 家族史的参与者中有 13% 的结果呈阳性。在首次出现 CKD 5 期的患者中，对精心策划的肾脏疾病基因组进行广泛分析的全基因组测序 (WGS) 在诊断上比肾活检提供更多信息，25 名参与者中有 24 名的活检结果尚无定论。结论在这个前瞻性确定的澳大利亚队列中，我们在 25% 的不明原因肾衰竭患者中发现了基因诊断......

更新日期：2024-05-03

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