title: A protocol for the identification and validation of novel genetic causes of kidney disease.
abstract: BACKGROUND
  Genetic renal diseases (GRD) are a heterogeneous and incompletely understood group of disorders accounting for approximately 10 % of those diagnosed with kidney disease. The advent of Next Generation sequencing and new approaches to disease modelling may allow the identification and validation of novel genetic variants in patients with previously incompletely explained or understood GRD.
  
  
  METHODS
  This study will recruit participants in families/trios from a multidisciplinary sub-specialty Renal Genetics Clinic where known genetic causes of GRD have been excluded or where genetic testing is not available. After informed patient consent, whole exome and/or genome sequencing will be performed with bioinformatics analysis undertaken using a customised variant assessment tool. A rigorous process for participant data management will be undertaken. Novel genetic findings will be validated using patient-derived induced pluripotent stem cells via differentiation to renal and relevant extra-renal tissue phenotypes in vitro. A process for managing the risk of incidental findings and the return of study results to participants has been developed.
  
  
  CONCLUSIONS
  This investigator-initiated approach brings together experts in nephrology, clinical and molecular genetics, pathology and developmental biology to discover and validate novel genetic causes for patients in Australia affected by GRD without a known genetic aetiology or pathobiology.
authors.affiliation: Kidney Health Service and Conjoint Kidney Research Laboratory, Royal Brisbane and Women's Hospital, Brisbane, Australia. Andrew.mallett@health.qld.gov.au.|Centre for Kidney Disease Research, Centre for Chronic Disease and CKD.QLD, School of Medicine, The University of Queensland, St Lucia, Australia. Andrew.mallett@health.qld.gov.au.|Institute for Molecular Bioscience, The University of Queensland, St Lucia, Australia. Andrew.mallett@health.qld.gov.au.|Kidney Health Service, Level 9, Ned Hanlon Building, Royal Brisbane and Women's Hospital, Butterfield Street, Herston, Brisbane, Qld, 4029, Australia. Andrew.mallett@health.qld.gov.au.
authors.forename: Andrew
authors.initials: A
authors.lastname: Mallett
authors.affiliation: Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Australia.
authors.forename: Chirag
authors.initials: C
authors.lastname: Patel
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St Lucia, Australia.|Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia.
authors.forename: Barbara
authors.initials: B
authors.lastname: Maier
authors.affiliation: Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Australia.
authors.forename: Julie
authors.initials: J
authors.lastname: McGaughran
authors.affiliation: Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Australia.|School of Medicine, Griffith University, Brisbane, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Gabbett
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St Lucia, Australia.|Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia.
authors.forename: Minoru
authors.initials: M
authors.lastname: Takasato
authors.affiliation: Centre for Kidney Disease Research, Centre for Chronic Disease and CKD.QLD, School of Medicine, The University of Queensland, St Lucia, Australia.
authors.forename: Anne
authors.initials: A
authors.lastname: Cameron
authors.affiliation: Queensland Child and Adolescent Renal Service, Lady Cilento Children's Hospital, Brisbane, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Trnka
authors.affiliation: Department of Nephrology, Children's Hospital at Westmead, Sydney and Sydney Medical School, The University of Sydney, Sydney, Australia.
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Alexander
authors.affiliation: Department of Nephrology, Westmead Hospital, Sydney and Sydney Medical School, The University of Sydney, Sydney, Australia.
authors.forename: Gopala
authors.initials: G
authors.lastname: Rangan
authors.affiliation: Department of Genetic Medicine, Westmead Hospital, Sydney and Sydney Medical School, The University of Sydney, Sydney, Australia.
authors.forename: Michel C
authors.initials: MC
authors.lastname: Tchan
authors.affiliation: Department of Anatomy and Developmental Biology, School of Biomedical Sciences, Monash University, Melbourne, Australia.
authors.forename: Georgina
authors.initials: G
authors.lastname: Caruana
authors.affiliation: Kidney Health Service and Conjoint Kidney Research Laboratory, Royal Brisbane and Women's Hospital, Brisbane, Australia.
authors.forename: George
authors.initials: G
authors.lastname: John
authors.affiliation: Department of Nephrology, Royal Children's Hospital, Melbourne, Australia.
authors.forename: Cathy
authors.initials: C
authors.lastname: Quinlan
authors.affiliation: Department of Nephrology, Children's Hospital at Westmead, Sydney and Sydney Medical School, The University of Sydney, Sydney, Australia.|Department of Genetic Medicine, Westmead Hospital, Sydney and Sydney Medical School, The University of Sydney, Sydney, Australia.
authors.forename: Hugh J
authors.initials: HJ
authors.lastname: McCarthy
authors.affiliation: Molecular Genetics Laboratory, Pathology Queensland and Royal Brisbane and Women's Hospital, Brisbane, Australia.
authors.forename: Valentine
authors.initials: V
authors.lastname: Hyland
authors.affiliation: Centre for Kidney Disease Research, Centre for Chronic Disease and CKD.QLD, School of Medicine, The University of Queensland, St Lucia, Australia.
authors.forename: Wendy E
authors.initials: WE
authors.lastname: Hoy
authors.affiliation: Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Australia.
authors.forename: Ernst
authors.initials: E
authors.lastname: Wolvetang
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St Lucia, Australia.
authors.forename: Ryan
authors.initials: R
authors.lastname: Taft
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St Lucia, Australia.
authors.forename: Cas
authors.initials: C
authors.lastname: Simons
authors.affiliation: Kidney Health Service and Conjoint Kidney Research Laboratory, Royal Brisbane and Women's Hospital, Brisbane, Australia.|Centre for Kidney Disease Research, Centre for Chronic Disease and CKD.QLD, School of Medicine, The University of Queensland, St Lucia, Australia.
authors.forename: Helen
authors.initials: H
authors.lastname: Healy
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St Lucia, Australia.|Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia.|Department of Paediatrics, University of Melbourne, Melbourne, Australia.
authors.forename: Melissa
authors.initials: M
authors.lastname: Little
mesh_terms: D006801:Humans; D007674:Kidney Diseases / Q000235:genetics*; D012107:Research Design; D054928:Validation Studies as Topic