Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT06200142 |
| Other study ID # |
ZOEMBA |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
December 10, 2019 |
| Est. completion date |
December 31, 2021 |
Study information
| Verified date |
December 2023 |
| Source |
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The goal of this clinical trial is to integrate genomic (WES/WGS) and other -omics
technologies in order to find the genetic causes, in 500 patients (children and adults) with
an unexplained metabolic phenotype in whom standard care (genetic and metabolic evaluation)
did not provide a diagnosis. The overall aim of this study is to diagnose patients with an
unknown metabolic phenotype. In addition, we want to provide evidence that the combination of
approaches and techniques used in this study will increase diagnostic yield compared to
current separated approaches.
All participants will undergo a multi-omics(WES, WGS and metabolomics) approach to solve the
unsolved genetic basis of their metabolic phenotype.
Description:
Rationale: Inborn Errors of Metabolism (IEM) are monogenic conditions in which the impairment
of a biochemical pathway is intrinsic to the pathophysiology of the disease. Organ
dysfunction results from intoxication and/or storage of metabolites, as well as a shortage of
energy and building blocks. Rapid diagnosis of IEM enables initiation of targeted treatment
(e.g. diet) slowing down or stopping the degenerative nature of the disease, resulting in
significantly reduction of morbidity and mortality. A diagnosis also enables prognostication,
access to community services and accurate genetic counselling for the patient and his/her
family. Diagnosing IEM can be a major challenge, because of phenotypic heterogeneity and
complex, expensive, diagnostic tests. Whole exome/ genome sequencing (WES/WGS) has
revolutionized diagnostics of rare diseases and IEM, but still gives a negative or
inconclusive result in >50% of cases. Addition of other omics technologies (metabolomics,
glycomics, lipidomics, epigenomics, transcriptomics, proteomics) with integrated
bioinformatics increases diagnostic yield, as it may point to the defective pathway allowing
scrutinizing genes in genomic data or vice versa: it generates evidence of the deleterious
functional impact of a DNA variants of unknown significance (VUS). In this study we will
unite our national expertises and apply a multi-omics approach to solve the unsolved genetic
basis of patients with a metabolic phenotype on a larger scale.
Objective: Integrating genomic (WES/WGS) and other -omics technologies in order to find the
genetic causes, in 500 patients (children and adults) with an unexplained metabolic phenotype
in whom standard care (genetic and metabolic evaluation) did not provide a diagnosis.
Study design: A prospective, diagnostic (deep phenotyping, WES/WGS and pan-omics) multicenter
cohort study.
Study population: (In)capacitated patients (all ages/both genders) with a clinical (and/or
family) history and abnormal additional examination (physical (neurological)/ biochemical/
radiological/ genetic) suspicious for an IEM, without diagnosis.
Main study parameters/endpoints: 1) identification of a genetic variant and alignment with
its biochemical and phenotypical abnormalities; 2) evaluating the diagnostic yield of
combined WES/WGS and omics techniques Methods used: Patients with unexplained metabolic
phenotypes are referred (on paper) and discussed by the ZOEMBA (Zoektocht naar Erfelijke
MetaBole Aandoening) team. Clinical phenotyping, bioinformatic reanalysis of WES data and
additional metabolomics will be performed in all participants. In case still no diagnosis is
made, a tailormade diagnostic plan is made combining deep WES, WGS, glycomics, lipidomics,
epigenomics, transcriptomics and/or proteomics leading to: a known IEM, a candidate variant
or no diagnosis. In case of a variant, additional functional studies (enzymatic assays,
targeted omics, CRISPR/CAS, cell lines) will be performed to confirm the effect of the
genetic variant on protein function. When still no diagnosis is established, matchmaking
(genetic/phenotypical) through international databases might lead to a diagnosis.
Nature and extent of the burden and risks associated with participation, benefit and group
relatedness:
The study involves collection of clinical data, reanalysis of previously analysed genetic
data, additional "omics" and functional testing. All participants will have between 1 and 3
clinical visits for this study (at the UMC of referral ) and a maximum of 2 telephone
appointments with the arts-onderzoeker. Whenever possible study visits will be combined with
regular hospital visits. Clinical data (clinical history, family history, physical
examination, consultations, additional laboratory and/or radiological investigations) will be
collected. A physical examination and blood and urine sampling will be performed in all
participants at their first study visit. Any other already available biological samples (eg
stored cell lines, dried blood spots, cerebrospinal fluid (CSF)) will be collected for
re-analysis. For a selection of patients a skin biopsy will be performed at the 2nd clinical
study visit for the use of functional studies. Potential burdens for participants are: the
additional study visit(s), diagnostic procedures (e.g. blood, urine sampling and skin
biopsy), as well as renewed (false) hope/uncertainty about finding a diagnosis. The potential
benefit for all participants include: the opportunity to establish a diagnosis providing
information on prognosis, (refinement of) management, genetic counselling with precise
recurrence risk and option(s) for prenatal diagnosis.
