A MALLETT1, C PATEL2,4, J CRAWFORD2,5, L HALE2,6,7, G HO2,8,9, K HOLMAN2,8, B BENNETTS2,8,9, M LITTLE2,6,7, I SMYTH2,10, C SIMONS2,5,6
1Royal Brisbane And Women’s Hospital, Stafford, Australia, 2KidGen Collaborative, Australian Genomics Health Alliance, Parville, Australia, 3Faculty of Medicine, The University of Queensland, Herston, Australia, 4Genetic Health Queensland, Royal Brisbane And Women’s Hospital, Herston, Australia, 5Institute for Molecular Bioscience, The University of Queensland, St Lucia, Australia, 6Murdoch Children’s Research Institute, Parkville, Australia, 7Department of Paediatrics and Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, Australia, 8Sydney Genome Diagnostics, Western Sydney Genetics Program, The Children’s Hospital at Westmead, Westmead, Australia, 9Discipline of Child & Adolescent Health; Discipline of Genetic Medicine, University of Sydney, Sydney, Australia, 10Monash Biomedicine Discovery Institute, Monash University, Clayton, Australia
Aim: To describe the collaborative process involved in translating new genetic causes of monogenic kidney disease into diagnostic clinical outcomes.
Background: The rate of novel nephrogene discovery has been accelerated by genomic research applications. Translating these discoveries into clinical diagnostic testing for patients with rare heritable kidney disease has been less clear or accelerated.
Methods: After informed consent, families with genetically unexplained heritable kidney disease were offered research whole exome/genome sequencing (WES/WGS) (HREC/14/QRBW/34). Custom in-house bioinformatic analysis identified putatively causative variants, which were confirmed independently in an accredited diagnostic laboratory.
Results: Two families had a genetic finding identified in the setting of novel nephrogenes reported during 2017. Family 1 has autosomal dominant renal agenesis, varying between unilateral and bilateral. Despite recruitment in 2014, having 5 affected family members and being recurrently re-analysed, a clear genetic cause had not been identified. On 26/07/2017, GREB1L was reported in association with this phenotype. A heterozygous GREB1L variant (c.4964T>C;p.(Ile1655Thr), ACMG Class4) was identified in all affected family members, diagnostically confirmed and reported to the participants on 19/12/2017 (146days later). Family 2, recruited in 2016, has a phenotype approximating Bartter Syndrome Type3 with autosomal recessive hypokalemic metabolic alkalosis and variable normocalciuria. On 03/07/2017, CLDN10 was reported in association with a similar phenotype. A homozygous CLDN10 variant (c.494G>C;p.(Gly165Ala), ACMG Class3) was identified in the affected family member, diagnostically confirmed and reported to the participants on 19/01/2018 (200days later).
Conclusions: These two families demonstrate the diagnostic power afforded by WES/WGS in ultra-rare and unresolved heritable kidney disease. Furthermore, they suggest that the time taken to translate new gene discoveries into clinical practice is meaningfully shortening.