Solve the Unsolved

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, 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/inconclusive result in >50% of cases. Addition of other omics
technologies (metabolomics, glycomics, lipidomics, epigenomics,
transcriptomics, proteomics) with integrated bio informatics has increased
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 VUS.

In this study we will unite our national expertise and apply a multi-omics
approach to solve the unsolved genetic basis of patients with a metabolic
phenotype on a larger scale.

Integrating genomic (WES/WGS) and other -omics technology in order to find the
genetic cause, in 500 patients (children and adults) with an unexplained
metabolic phenotype in whom standard care (genetic and metabolic evaluation)
did not provide a diagnosis.

A prospective, diagnostic (deep phenotyping, WES/WGS and pan-omics) multicenter
cohort study.

Patients with unexplained metabolic phenotypes are referred (on paper) and
discussed by the Solve the Unsolved (StU) team. After informed consent,
clinical phenotyping, bioinformatic reanalysis of WES data and additional
metabolomics will be performed in all participants. In case of no diagnosis, a
tailor made diagnostic plan is made combining deep WES, WGS, glycomics,
lipidomics, epigenomics, transcriptomics and/or proteomics Combination of these
studies can lead to: 1) a known IEM, 2) a candidate variant, 3) still no
diagnosis.

In case of a variant, additional functional studies (enzymatic assays, targeted
omics, CRISPR/CAS, cell lines) will be used to confirm the effect of the
genetic variant on protein function leading to definite. If still undiagnosed
matchmaking (genetic/phenotypical) through international databases might lead
to diagnosis.

The study involves collection of clinical data, reanalysis of previously
analysed genetic data, additional *omics* and functional testing.
All participants will have at least 1 and at maximum 3 clinical study visits
(located at the hospital of treatment) and maximum 2 telephone appointments
with the arts-onderzoeker. Whenever possible clinical 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, 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. In a selection of
patients a skin biopsy will be performed at the 2nd clinical study visit for
the use of functional studies.

The additional study visit and diagnostic procedures (e.g. blood, urine
sampling and skin biopsy) and its associated risks, as well as renewed (false)
hope/uncertainty about finding a diagnosis are potential burdens for
participants. 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.