Zoektocht Naar Erfelijke MetaBole Aandoening (Dutch)/ Solve The Unsolved (English)

NCT06200142 | Completed DMC

• 1 other identifier: ZOEMBA
• Study Type: interventional
• Target: 334
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Inherited Metabolic Disorders

Keywords

WES; WGS; Metabolomics; Diagnoses

Outcome Measures

Primary Outcomes (1)

• Diagnostic yield

  Number of patients diagnosed

  3 years

Study Arms (1)

The unsolved

EXPERIMENTAL

(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.

Diagnostic Test: Untargeted metabolomics; Genetic: WES and WGS

Interventions

Untargeted metabolomics DIAGNOSTIC_TEST

Untargeted metabolomics in bloodspots and in plasma

The unsolved

WES and WGS GENETIC

WES reanalysis and WGS analysis

Also known as: Genomics

The unsolved

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with an unexplained metabolic phenotype defined as: neurological symptoms and/or abnormalities on (physical) examination suggestive of an inborn error of metabolism (energy deficiency, intoxication type or storage type):
• Energy deficiency: neurological (repeated rhabdomyolysis, verified exercise intolerance, neuropathy, myopathy, ataxia), ophthalmological (retinitis pigmentosa (RP)), otological (hearing loss, deafness), endocrine (hypoparathyroidism, hypoglycemia) Intoxication: neurological (encephalopathy, regression, movement disorder, psychiatric symptoms), ophthalmological (lens luxation), organic (liver and kidney function abnormalities) Storage: neurological (regression, psychiatric symptoms), ophthalmological (cataract/corneal clouding), skin (angiokeratomas), blood (cytopenias), organic (hepatosplenomegaly, cardiac hypertrophy, skeletal abnormalities, short stature, coarse facial features, umbilical/inguinal hernia)
• AND / OR one or more of the following suggesting a deficient metabolic pathway or process:
• abnormal metabolites in body fluids (CSF, urine, blood)
• functional studies at a biochemical/cellular level indicative of a metabolic deficiency (e.g. respiratory chain complex analysis)
• organ dysfunction (e.g. liver or kidney failure)
• an abnormal clinical function test (protein loading test, fasting test, meal test, validated exercise test, non-ischaemic underarm test)
• abnormalities on imaging (neuro-imaging (including spectroscopy); X-rays (dysostoses or other bone abnormalities); ultrasound (enlarged liver/spleen))
• a VUS (variant of unknown significance) in a gene involved in metabolism
• AND no diagnosis despite extensive clinical, metabolic and genetic investigations
• SNP-array/array-CGH: inconclusive results
• metabolic screening according to up to date clinical protocols: inconclusive results
• WES (open or gene panel): no class 4 or 5 variants in a known (OMIM annotated) disease related gene that can fully explain the phenotype of the patient

You may not qualify if:

• A patient will be excluded from participation in this study if:
• after discussion by the ZOEMBA team (see Methods) he/she is suspected to have:
• a genetic condition for which there is a simpler and more cost-effective test available for diagnosis
• a complex genetic disorder (caused by a combination of multiple genes and/or environmental influences)
• a condition that is thought to be caused by factors that are non-genetic, such as infection, injury or toxic exposure
• he/she is unable to follow the study protocol (e.g. additional blood samples)

Sponsors & Collaborators

• Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA): lead
• Stichting Metakids: collaborator

Study Sites (1)

Amsterdam UMC

Amsterdam, Netherlands

Location

Related Links

• United for Metabolic Diseases

MeSH Terms

Conditions

Disease

Interventions

Whole Genome Sequencing; Genome

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Sequence Analysis, DNA; Sequence Analysis; Genetic Techniques; Investigative Techniques; Genetic Structures; Genetic Phenomena

Study Officials

• Clara DM van Karnebeek, Professor

  Amsterdam UMC and United for Metabolic Diseases (UMD)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: (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.

Study Record Dates

• First Submitted: December 29, 2023
• First Posted: January 10, 2024
• Study Start: December 10, 2019
• Primary Completion: December 31, 2021
• Study Completion: December 31, 2021
• Last Updated: January 10, 2024

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will share
• Time Frame: 3 years
• Access Criteria: RD-connect access

Locations

NL (1)