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Trial registered on ANZCTR


Registration number
ACTRN12615000140550
Ethics application status
Approved
Date submitted
16/01/2015
Date registered
13/02/2015
Date last updated
7/04/2024
Date data sharing statement initially provided
19/11/2018
Date results information initially provided
13/04/2023
Type of registration
Retrospectively registered

Titles & IDs
Public title
Next Generation Sequencing and Induced Pluripotent Stem Cell Applications in Genetic and Inheritable Forms of Renal Disease
Scientific title
Next Generation Sequencing and Induced Pluripotent Stem Cell Applications to clarify diagnosis for those with Genetic and Inheritable Forms of Renal Disease
Secondary ID [1] 285988 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Inherited Kidney Disease 293936 0
Condition category
Condition code
Renal and Urogenital 294236 294236 0 0
Kidney disease
Human Genetics and Inherited Disorders 294330 294330 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This project will attempt to elucidate the genetic basis for inheritable kidney disease using next generation sequencing (NGS). The NGS employed may be targeted to a panel of genes of interest, to the whole exome (i.e. canonical protein-coding genes), or the entire genome. The patient cohort will include those whose family history and/or phenotype strongly suggests a genetic aetiology and in whom routine genetic testing is:
a) not clinically available
b) not feasible given high genetic heterogeneity of the suspected disorder, or
c) has failed to arrive at a diagnosis for the likely disorder.

Patients will be seen and assessed by a nephrologist and/or clinical geneticist in a Renal Genetics Clinic. Patients meeting minimum requirements for participation will be offered enrolment to the study and informed consent will be obtained. Once consent has been given, a DNA sample will be obtained via a blood test or buccal swab. The DNA will be analysed using NGS technologies. Where possible, family members including parents, siblings and possibly offspring of the affected individual will be recruited and included in the NGS testing. Genomic testing on first-degree relatives is necessary in most cases for the accurate interpretation of genetic variants found in the affected patient.
Intervention code [1] 290964 0
Diagnosis / Prognosis
Comparator / control treatment
Those with inherited kidney disease who have previously undergone standard renal genetic testing.
This historical cohort data be collected from quality assurance and audit activity of the local renal genetics clinic up to the date of most recent audit prior to first study enrolment (1 July 2013 to 1 June 2014).
Control group
Historical

Outcomes
Primary outcome [1] 294040 0
Identification of a novel genetic cause for inherited kidney disease utilising NGS (WES/WGS) of a patient's DNA sample, subsequently submitted for confirmation (Sanger Sequencing) in a clinically accredited laboratory
Timepoint [1] 294040 0
1year
Secondary outcome [1] 312391 0
Validation of a novel genetic cause for inherited kidney disease by either functional validation (fibroblast, iPSC, etc) and/or correlation with similar cases with the same disease and genetic variants
Timepoint [1] 312391 0
2yrs

Eligibility
Key inclusion criteria
Two groups of individuals will be recruited for this study:
- Candidates for participation in the protocol will be affected individuals whose family history and/or phenotype strongly suggests a genetic aetiology and in whom routine genetic testing is:
a) not clinically available
b) not feasible given the suspected disorder has high genetic heterogeneity, or
c) if specific testing for the likely disorder has already failed to arrive at a diagnosis.

- First-degree relatives of participating patients (father, mother, siblings, or sons and daughters of the patients).


Patients will be seen and assessed by a nephrologist and/or clinical geneticist in a Renal Genetics Clinic.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
- Declination to participate in the study
- An insufficient number of direct relatives willing/able to participate in the study. In most cases inclusion in this study will require the participation of the patient and both parents. However, in some cases a combination of factors including the structure of the family pedigree, the suspected mode of inheritance, and information available regarding the specific disease may provide the required level of genetic information and therefore warrant inclusion in the study. This will be determined on a case-by-case basis by the Principal Investigators.

Study design
Purpose of the study
Diagnosis
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Participants will be identified through standard clinical contact at the RBWH Department of Renal Medicine, Queensland Conjoint Renal Genetics Clinic/Service or Genetic Health Queensland.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
N/A
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Upon recruitment, all participants will be assigned a unique identifier for the purposes of this study by the clinical service. A confidential database, maintained on a Queensland Health server, will link participant identifying information and their project identifier code. Project team members from The University of Queensland will receive all samples and case details anonymously, with the exception of the unique identifier. Only the clinical service will know the identity of the patient samples.

The treating clinician of each affected participant will prepare a precis of the clinical features of the participant, the family structure and any relevant family history. This information is required to make informed evaluations of the genetic variant data derived from each family. This precis will not include any identifying information other than participant project codes. This document will be provided to The University of Queensland research team when DNA samples are provided.
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
DNA Sequence data will be analysed from all participating members of a family in parallel. Comprehensive quality control metrics are derived for each sample to ensure the quality of the sequence data. All sequence reads are compared to the human reference sequence and used to identify variant positions where the participant DNA is different from the reference genome. Each variant position within a family is then evaluated based on its likelihood to contribute to the disease of the affected individual/s. This assessment will be assisted by the Variant Assessment Tool, an internal software tool developed by the Simons laboratory that integrates family genetic variant segregation details with external information sources such the frequency of the allele in published control populations, the predicted impact of the variant on protein coding sequences and genes known to be associated with genetic disorders.
The projected number of participants is based upon recruiting in trios (mother, father, offspring) or larger families. The expected success rate of this approach is 25-50% from past similar studies in other undiagnosed and rare genetic disorders.
The number of participants is also limited by the capacity for genetic sequencing and cellular validation which can be achieved with present research funding. Targeting ~30 families gives an expected chance of discovering a novel genetic diagnosis in 10 of those families. Further, the selection of highly phenotyped families with an appropriate family structure further increases the chance of securing such a novel genetic diagnosis, even if this also results in selecting only a relatively small number of families (~30).

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
29/04/2014
Actual
2/06/2014
Date of last participant enrolment
Anticipated
Actual
13/11/2020
Date of last data collection
Anticipated
31/12/2025
Actual
Sample size
Target
300
Accrual to date
Final
236
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 3334 0
Royal Brisbane & Womens Hospital - Herston
Recruitment postcode(s) [1] 9123 0
4029 - Royal Brisbane Hospital

Funding & Sponsors
Funding source category [1] 290575 0
Charities/Societies/Foundations
Name [1] 290575 0
RBWH Foundation
Country [1] 290575 0
Australia
Funding source category [2] 290577 0
Charities/Societies/Foundations
Name [2] 290577 0
Pathology Queensland SERTF
Country [2] 290577 0
Australia
Funding source category [3] 290578 0
Charities/Societies/Foundations
Name [3] 290578 0
Alport Foundation of Australia
Country [3] 290578 0
Australia
Funding source category [4] 290579 0
Hospital
Name [4] 290579 0
RBWH Conjoint Renal Research Laboratory
Country [4] 290579 0
Australia
Primary sponsor type
Hospital
Name
Genetic Health Queensland, RBWH
Address
Level 6, Block 7
RBWH
Herston, QLD, 4029
Country
Australia
Secondary sponsor category [1] 289265 0
University
Name [1] 289265 0
University of Queensland
Address [1] 289265 0
Simons Lab, UQ IMB
Queensland Bioscience Precinct Delivery Dock
Building 80, Services Road, The University of Queensland
St Lucia QLD 4072
Country [1] 289265 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292215 0
RBWH HREC
Ethics committee address [1] 292215 0
Human Research Ethics Office
Level 7, Block 7
Royal Brisbane and Women's Hospital
Herston, QLD, 4029
Ethics committee country [1] 292215 0
Australia
Date submitted for ethics approval [1] 292215 0
Approval date [1] 292215 0
10/03/2014
Ethics approval number [1] 292215 0
HREC/14/QRBW/34
Ethics committee name [2] 292216 0
UQ Institutional Human Research Ethics Committee
Ethics committee address [2] 292216 0
UQ Institutional Human Research Ethics Committee
The University of Queensland
St. Lucia, QLD, 4072
Ethics committee country [2] 292216 0
Australia
Date submitted for ethics approval [2] 292216 0
Approval date [2] 292216 0
03/04/2014
Ethics approval number [2] 292216 0
2014000453

Summary
Brief summary
Recent advances in genetic sequencing technology have resulted in remarkable improvements in the speed, throughput and cost of sequencing all, or part, of an individual's genome. Our hypothesis is that emerging high throughput sequencing technologies will lead to the rapid identification of new disease genes in genetic renal disease.

This project will attempt to elucidate the genetic basis for inheritable kidney disease using next generation sequencing (NGS). The NGS employed may be targeted to a panel of genes of interest, to the whole exome (i.e. canonical protein-coding genes), or the entire genome. The patient cohort will include those whose family history and/or phenotype strongly suggests a genetic aetiology and in whom routine genetic testing is:
a) not clinically available
b) not feasible given high genetic heterogeneity of the suspected disorder, or
c) has failed to arrive at a diagnosis for the likely disorder.

Patients will be seen and assessed by a nephrologist and/or clinical geneticist in a Renal Genetics Clinic. Patients meeting minimum requirements for participation will be offered enrolment to the study and informed consent will be obtained. Once consent has been given, a DNA sample will be obtained via a blood test or buccal swab. The DNA will be analysed using NGS technologies. Where possible, family members including parents, siblings and possibly offspring of the affected individual will be recruited and included in the NGS testing. Genomic testing on first-degree relatives is necessary in most cases for the accurate interpretation of genetic variants found in the affected patient.

Disease-causing mutations will be specifically sought in genes thought to be related to the patient's condition. If found, these variants will be confirmed with specific testing in a clinical laboratory, if available. Validation studies may be performed in a research capacity on selected novel potentially disease-causing variants or where disease pathobiology is not known. This will include patient-derived induced pluripotent stem cell (iPSC) validation after further patient consent for skin biopsy, urine sample, blood sample or buccal swab. iPSC technology enables ex vivo “disease in a dish” cellular and functional research of human disease owing to the ability to redifferentiate iPSC to many different cell types and thus model and validate how a genetic variant may mediate disease.

Mutations previously reported to be disease-causing may also be discovered in genes not related to the patient's condition. Participants will be informed of known or expected, disease-causing variants in primary genes of interest. If chosen at the time of consent, participants will be informed of mutations in genes predicted to be associated with unrelated disease, and for which intervention is available.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 54142 0
Dr Andrew Mallett
Address 54142 0
Department of Renal Medicine
Lev 9 Ned Hanlon Building
RBWH
Herston, QLD, 4029
Country 54142 0
Australia
Phone 54142 0
+61 7 3646 8111, +61 7 3646 8576
Fax 54142 0
Email 54142 0
andrew.mallett@health.qld.gov.au
Contact person for public queries
Name 54143 0
Dr Andrew Mallett
Address 54143 0
Department of Renal Medicine
Lev 9 Ned Hanlon Building
RBWH
Herston, QLD, 4029
Country 54143 0
Australia
Phone 54143 0
+61 7 3646 8111, +61 7 3646 8576
Fax 54143 0
Email 54143 0
andrew.mallett@health.qld.gov.au
Contact person for scientific queries
Name 54144 0
Dr Andrew Mallett
Address 54144 0
Department of Renal Medicine
Lev 9 Ned Hanlon Building
RBWH
Herston, QLD, 4029
Country 54144 0
Australia
Phone 54144 0
+61 7 3646 8111, +61 7 3646 8576
Fax 54144 0
Email 54144 0
andrew.mallett@health.qld.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.