In this study, we aim to improve the genetic diagnosis of patients with genetic renal tubulopathy-related disorders. We hypothesize that a higher diagnostic yield can be obtained by genetic re-screening of patients using the updated renal gene panel…
ID
Source
Brief title
Condition
- Renal and urinary tract disorders congenital
- Nephropathies
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
* Patient data, including but not limited to primary phenotype, original
clinical diagnosis, family history, age, and sexs
* Genetic profiles of patients, as obtained using previous (routine) genetic
testing, or newly obtained whole exome sequencing, mitochondrial DNA screening,
and whole genome sequencing data
Secondary outcome
* To determine the ion transporter function of the patients in specific parts
of the renal tubules based on different tests, e.g., the
thiazide, furosemide, furosemide-fludrocortisone, and DDAVP tubular function
tests. These tests will be performed based on the patient's specific phenotype,
or after a genetic variant (either an already known variant or a VUS) was found
that is thought to hamper tubule function. To get a better understanding of the
phenotype as well as the effect of the variant on the phenotype and the
specific parts of the renal tubules.
* To identify and investigate novel mutations both within and outside of the
standard renal WES panel.
* In case of a mitochondrial variant with unknown significance, to determine
the heteroplasmy level of a mtDNA variant in blood, urine, and fibroblasts of
participants, as well as the mitochondrial function based on fibroblast culture
from skin biopsies.
* To investigate the use of advanced urine diagnostics to improve screening of
patients using urinary extracellular vesicles (uEVs) and adult stem cells
(ASCs).
* Laboratory parameters will mainly be retrieved from the patient records by
the treating physician and anonymously shared with the research team. When the
necessary evaluations are not recent or not available, blood will be drawn for
these laboratory evaluations at the Radboudumc. For each analysis, the values
will be compared to normal reference values.
Background summary
Renal tubulopathy-related disorders are a heterogenous group of genetic
disorders, in which the renal tubular transport is disturbed.
Consequently, patients present with disruption of the water, electrolyte,
and/or acid-base balance, resulting in a wide-range of
symptoms. Diagnosis of renal tubulopathy-related disorders is most often based
on a combination of clinical symptoms
(phenotyping) and genetic screening. However, in a subset of patients, the
genetic diagnosis cannot be established. Nowadays the
screening is most often done with either gene-specific testing or with whole
exome sequencing (WES) using subsequent gene panel
filters that include genes known to be related to renal diseases. Nevertheless,
this only includes nuclear encoded genes known to
cause kidney disease. As a consequence, gene mutations in mitochondrial DNA,
mutations outside of the exons, and mutations
outside the gene panel, are currently being missed. The lack of diagnosis
results in basic treatment of the symptoms, which can be
enough but when the causative mechanism is not known, the proper treatment is
not always found. In addition, lack of diagnosis is
both a psychological burden and a practical problem (sick leave, insurance
issues) for patients. Thus, improving genetic screening
will not only increase our knowledge about current (and possible novel) renal
tubulopathy-related disorders, but it will also affect
patient quality of life and improve (future) treatment options
Study objective
In this study, we aim to improve the genetic diagnosis of patients with genetic
renal tubulopathy-related disorders. We hypothesize that a higher diagnostic
yield can be obtained by genetic re-screening of patients using the updated
renal gene panel, expanding the genetic screening to include whole exome, whole
genome, and mitochondrial DNA screening. The secondary objective is to identify
and investigate novel mutations both within and outside of the previously
applied genetic screening. Furthermore, if applicable, we will broaden the
phenotyping by doing additional (clinical, functional, or histological) tests
and we will investigate advanced urine diagnostics.
Study design
Exploratory study
Study burden and risks
For some patients there will be no physical risk at all, due to the use of
previously obtained genetic data and/or previously obtained material. Depending
on the patient, the study procedure will have different steps and patients can
opt-out at all moments. The physical risk of this study is mainly determined by
the tubular ion transport function tests, due to administration of e.g.,
thiazide, which is low. The Radboudumc Expertise Center for Rare Kidney
Disorders has validated protocols for such renal tubular tests, which include
instructions on how to prevent and/or detect these complications. The rest of
this study has little physical risk but does have some physical burden, such as
collection of blood samples and 24-hour urine, if applicable a skin biopsy, as
well as potential extra hospital visits. In addition, there is also a
psychological burden connected to the study. Although all patients have been
genetically tested by the Radboudumc, not all are currently actively followed
at our outpatient clinic. So, they will have to be contacted again, which could
be unexpected for these patients. The genetic testing also carries some
psychological burden, such as chance of secondary findings or lack of diagnosis
after testing. Patients that agree to accessing their genetic material, are not
obliged to continue in any of the other steps, whether this is additional
genetic testing or functional testing, and can of course retract consent at any
time during or after this study. Next to this, an up-to-date bioinformatic
filter will be used to reduce the chance of secondary findings by hiding known
pathogenic variants (not related to renal tubulopathies) that otherwise would
have to be reported to the patient. Lastly, all patients will be informed
either by the researchers under supervision of a clinical geneticist or by a
clinical geneticist, about the risk of secondary findings.
Geert Grooteplein 10
Nijmegen 6525 GA
NL
Geert Grooteplein 10
Nijmegen 6525 GA
NL
Listed location countries
Age
Inclusion criteria
* The patient must have had genetic screening that did not result in a genetic
diagnosis explaining the phenotype, performed at the Radboudumc
* The patient must have clinical proof of renal loss of salts, HCO3-, acid,
glucose, amino acids, low molecular weight proteins, and/or water, as such
presenting with a phenotype that suggests a renal tubulopathy is present
Exclusion criteria
Patients with a previous (genetic) diagnosis fully explaining their renal
tubulopathy-related phenotype
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL87808.091.24 |