THE EMERGING ROLE OF WHOLE GENOME INVESTIGATION TO IDENTIFY UNDETECTED NEPHROPATHIES – THE HIDDEN STUDY

A MALLETT 1,2,3,4, A MALLAWAARACHCHI 4,5,6, Z STARK Z4,7,8,9, C SIMONS 4,8,9, C QUINLAN 4,8,9,10, C PATEL 4,11, ON BEHALF OF THE KIDGEN COLLABORATIVE4

1Townsville University Hospital, Douglas, Australia, 2James Cook University , Townsville, Australia, 3Institute for Molecular Bioscience & Faculty of Medicine, The University of Queensland, Brisbane, Australia, 4The KidGen Collaborative, Australian Genomics Health Alliance, Parkville, Australia, 5Garvan Institute, Sydney, Australia, 6Royal Prince Alfred Hospital, Sydney, Australia, 7Victorian Clinical Genetics Service, Melbourne, Australia, 8Murdoch Children’s Research Institute, Melbourne, Australia, 9University of Melbourne, Melbourne, Australia, 10Royal Children’s Hospital, Melbourne, Australia, 11Genetic Health Queensland, Royal Brisbane & Women’s Hospital, Brisbane, Australia

Aim: To determine the diagnostic yield of clinical whole genome sequencing (WGS) in individuals with unexplained end stage kidney disease (ESKD).

Background: 5% of Australian and New Zealand patients commencing kidney replacement therapy have an uncertain kidney disease aetiology. New approaches and tools are required to resolve such diagnostic odysseys. WGS is an emerging diagnostic technology whose role in this setting is unclear.

Methods: Adult and paediatric patients reaching Chronic Kidney Disease Stage 5 before 51 years of age without an identified aetiology were prospectively recruited through a national network of 18 clinics. Eligibility was determined by a national clinical committee based on pre-specified criteria.

Clinically-accredited WGS analysis was undertaken with a curated “KidneyOme” virtual panel of genes associated with Mendelian kidney disorders. A genomic diagnosis constituted a KidneyOme result of pathogenic or likely pathogenic variant/s of appropriate zygosity.

Results:168 individuals were referred (2018-2021) of whom 147 were approved and 104 consented. Of these, 40 (38.5%) were female and median age was 43yrs; 41 (39.4%) reached ESKD before 30yrs and 63 (60.6%) had undergone native kidney biopsy. Of 50 results returned to date, 7 (14%) were diagnostic, including both autosomal dominant (4/7) and recessive (3/7) inheritance patterns with 6/7 having a family history of CKD. A further 14/50 had variants of uncertain significance. One diagnosis was due to a copy number variation.

The KidneyOme virtual panel curation of 384 genes is publicly available in PanelApp-Australia.

Conclusion: One in seven patients with ESKD of uncertain aetiology had an undetected underlying monogenic cause for their kidney disease. Application of KidneyOme with WGS has diagnostic utility and should be considered in younger patients with unexplained renal failure..


Biography:

Professor Mallett is an Adult Nephrologist with a special interest in genetic kidney disease and nephrogenetics. Having been a Churchill Fellow and an RACP Foundation Jacquot Research Establishment Fellow, he has a strongly emerging clinical and research profile in this field. Currently Professor of Medicine (JCU) and Clinical Fellow (IMB at UQ), Prof Mallett is also National Director of the KidGen Collaborative, and, Director of Clinical Research and Nephrologist (Townsville University Hospital). He is committed to improving the understanding of inherited kidney disease as well as the clinical care and outcomes of Australians affected by it.

 

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