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出境医 / 临床实验 / Whole Genome Trio Sequencing as a Standard Routine Test in Patients With Rare Diseases - "GENOME FIRST APPROACH"
Whole Genome Trio Sequencing as a Standard Routine Test in Patients With Rare Diseases - "GENOME FIRST APPROACH"
Study Description
Brief Summary:
The GENOME FIRST APPROACH project will enroll patients (n = 450) and their healthy parents with unclear molecular cause of the disease, suspected genetic cause of the disease and the healthy parents of those affected for trio analysis (N in total 1350).
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Rare Diseases Genetic Predisposition | Genetic: WGS-Diagnostic | Not Applicable |
Detailed Description:
In the GENOME FIRST APPROACH (monocentric, prospective, open-label diagnostic) project, patients with molecularly undiagnosed diseases will diagnostically be analyzed by Whole Genome Sequencing (WGS)-trio analysis. The following questions will be leading the project:
Primary:
• Efficacy of WGS trio analysis in different clinical indications
Secondary:
- Systematically benchmark WGS analysis to detect genetic variations compared to WES and single nucleotide polymorphism (SNP) array analysis,
- Expand the analysis from coding single-nucleotide variants (SNVs) to regulatory mutations, structural variants (SVs), and low complexity regions,
- Validate the efficacy of clinical genome trio sequencing in a routine diagnostic setting,
- Analyse whether 42x coverage has the potential to discover mosaicism as disease causing mechanism,
- Further develop algorithms for integrative analyses of Trio-WGS data with Ribonucleic acid- sequencing (RNA-seq),
- Identify de novo alterations and novel disease mechanisms,
- Gain fundamental new insights into disease mechanisms and cellular biology,
- Combine WGS with further Omics methods to improve genetic diagnostics of future rare disease patients, and
- Explore overall financial costs and time to report conclusive data to the patients of the Trio-WGS approach compared to traditional multistep diagnostic approaches using single-gene, panel, whole-exome sequencing (WES) and chromosomal microarray (CMA) (SNP array, array-based comparative genomic hybridization (arrayCGH)) analysis.
In addition, healthy parents of the subjects will be included in the project to perform parent-child (trio) analyzes.
Study Design
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 1350 participants |
| Allocation: | Non-Randomized |
| Intervention Model: | Parallel Assignment |
| Intervention Model Description: | Cohort 1: IQ < 70 with and without malformations, syndromic and non-syndromic Cohort 2: Retinitis pigmentosa, achromatopsy, Bardet-Biedl syndrome, Usher syndrome, congenital stationary night blindness, LCA, macula degeneration, rod/ cone dystrophies, opticus atrophy Cohort 3: Rare paediatric solid cancers as melanoma, carcinoma of the gastrointestinal tract, tumours of the salivary gland and pancreatic tumors in children. Plus: their respective parents |
| Masking: | None (Open Label) |
| Primary Purpose: | Basic Science |
| Official Title: | Whole Genome Trio Sequencing as a Standard Routine Test in Patients With Rare Diseases - "GENOME FIRST APPROACH" |
| Actual Study Start Date : | October 1, 2019 |
| Estimated Primary Completion Date : | December 2021 |
| Estimated Study Completion Date : | December 2022 |
Arms and Interventions
| Arm | Intervention/treatment |
|---|---|
|
Cohort 1: Intellectual disability
Genetic: WGS Diagnostic Blood take for genetic diagnostic.
|
Genetic: WGS-Diagnostic
Blood sampling, shot clinical characterization, WGS-based trio sequencing, NGS analysis and other omics analysis (transcriptomics, proteomics, metabolomics), functional cell biology studies (for example in fibroblast cultures), RNA-seq.
|
|
Cohort 2 Retinal diseases
Genetic: WGS Diagnostic Blood take for genetic diagnostic.
|
Genetic: WGS-Diagnostic
Blood sampling, shot clinical characterization, WGS-based trio sequencing, NGS analysis and other omics analysis (transcriptomics, proteomics, metabolomics), functional cell biology studies (for example in fibroblast cultures), RNA-seq.
|
|
Cohort 3: Rare tumors in childhood
Genetic: WGS Diagnostic Blood take for genetic diagnostic.
|
Genetic: WGS-Diagnostic
Blood sampling, shot clinical characterization, WGS-based trio sequencing, NGS analysis and other omics analysis (transcriptomics, proteomics, metabolomics), functional cell biology studies (for example in fibroblast cultures), RNA-seq.
|
Outcome Measures
Primary Outcome Measures :
- Full genomic sequence analysis carried out by Whole Genome Sequencing (WGS) [ Time Frame: Day 1 ]Number of genomic variants in disease and health parents by WGS (a Next-Generation Sequencing Technology, NGS)
Secondary Outcome Measures :
- Genome sequencing [ Time Frame: Day 1 ]Verification of the genetic causes of unclear genetic diseases by clinical genome sequencing
- De novo alterations [ Time Frame: Day 1 ]Number of de novo alterations in genome of the enrolled population
Eligibility Criteria
| Ages Eligible for Study: | Child, Adult, Older Adult |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
- Unclear molecular cause of the disease
- Suspected genetic cause of the disease
- Healthy parents of those affected for trio analysis Cohort 1: IQ < 70 with and without malformations, syndromic and non-syndromic Cohort 2: Retinitis pigmentosa, achromatopsy, Bardet-Biedl syndrome, Usher syndrome, congenital stationary night blindness, LCA, macula degeneration, rod/ cone dystrophies, opticus atrophy Cohort 3: Rare paediatric solid cancers as melanoma, carcinoma of the gastrointestinal tract, tumours of the salivary gland and pancreatic tumors in children.
Exclusion Criteria:
Cohort 1: Toxic causes (drugs, infections) Cohort 2: patients with non-genetic forms of blindness Cohort 3: adult cancer, blood cancer
- Missing informed consent of the patient/ legal guardian
- Missing samples of both parents
- Previous WES or panel analysis-
Contacts and Locations
Contacts
| Contact: Olaf Riess, Prof. Dr. | +49 7071 298 ext 72323 | olaf.riess@med.uni-tuebingen.de | |
| Contact: Tobias Haack, Dr. | +49 7071 298 ext 77696 | tobias.haack@med.uni-tuebingen.de |
Locations
| Germany | |
| University Hospital Tübingen | Recruiting |
| Tübingen, Germany, 72076 | |
| Contact: Olaf Rieß, Prof. Dr. +49 7071-297 ext 2323 olaf.riess@med.uni-tuebingen.de | |
| Contact: Tobias Haack, Dr. +49 7071-297 tobias.haack@med.uni-tuebingen.de | |
Sponsors and Collaborators
University Hospital Tuebingen
Investigators
| Study Director: | Olaf Riess, Prof. Dr. | University Hospital Tübingen |
| Tracking Information | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| First Submitted Date ICMJE | May 9, 2019 | ||||||||
| First Posted Date ICMJE | May 17, 2019 | ||||||||
| Last Update Posted Date | November 5, 2020 | ||||||||
| Actual Study Start Date ICMJE | October 1, 2019 | ||||||||
| Estimated Primary Completion Date | December 2021 (Final data collection date for primary outcome measure) | ||||||||
| Current Primary Outcome Measures ICMJE |
Full genomic sequence analysis carried out by Whole Genome Sequencing (WGS) [ Time Frame: Day 1 ] Number of genomic variants in disease and health parents by WGS (a Next-Generation Sequencing Technology, NGS)
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| Original Primary Outcome Measures ICMJE | Same as current | ||||||||
| Change History | |||||||||
| Current Secondary Outcome Measures ICMJE |
|
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| Original Secondary Outcome Measures ICMJE | Same as current | ||||||||
| Current Other Pre-specified Outcome Measures | Not Provided | ||||||||
| Original Other Pre-specified Outcome Measures | Not Provided | ||||||||
| Descriptive Information | |||||||||
| Brief Title ICMJE | Whole Genome Trio Sequencing as a Standard Routine Test in Patients With Rare Diseases - "GENOME FIRST APPROACH" | ||||||||
| Official Title ICMJE | Whole Genome Trio Sequencing as a Standard Routine Test in Patients With Rare Diseases - "GENOME FIRST APPROACH" | ||||||||
| Brief Summary | The GENOME FIRST APPROACH project will enroll patients (n = 450) and their healthy parents with unclear molecular cause of the disease, suspected genetic cause of the disease and the healthy parents of those affected for trio analysis (N in total 1350). | ||||||||
| Detailed Description |
In the GENOME FIRST APPROACH (monocentric, prospective, open-label diagnostic) project, patients with molecularly undiagnosed diseases will diagnostically be analyzed by Whole Genome Sequencing (WGS)-trio analysis. The following questions will be leading the project: Primary: • Efficacy of WGS trio analysis in different clinical indications Secondary:
In addition, healthy parents of the subjects will be included in the project to perform parent-child (trio) analyzes. |
||||||||
| Study Type ICMJE | Interventional | ||||||||
| Study Phase ICMJE | Not Applicable | ||||||||
| Study Design ICMJE | Allocation: Non-Randomized Intervention Model: Parallel Assignment Intervention Model Description: Cohort 1: IQ < 70 with and without malformations, syndromic and non-syndromic Cohort 2: Retinitis pigmentosa, achromatopsy, Bardet-Biedl syndrome, Usher syndrome, congenital stationary night blindness, LCA, macula degeneration, rod/ cone dystrophies, opticus atrophy Cohort 3: Rare paediatric solid cancers as melanoma, carcinoma of the gastrointestinal tract, tumours of the salivary gland and pancreatic tumors in children. Plus: their respective parents Primary Purpose: Basic Science |
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| Condition ICMJE |
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| Intervention ICMJE | Genetic: WGS-Diagnostic
Blood sampling, shot clinical characterization, WGS-based trio sequencing, NGS analysis and other omics analysis (transcriptomics, proteomics, metabolomics), functional cell biology studies (for example in fibroblast cultures), RNA-seq.
|
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| Study Arms ICMJE |
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| Publications * | Not Provided | ||||||||
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* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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| Recruitment Information | |||||||||
| Recruitment Status ICMJE | Recruiting | ||||||||
| Estimated Enrollment ICMJE |
1350 | ||||||||
| Original Estimated Enrollment ICMJE | Same as current | ||||||||
| Estimated Study Completion Date ICMJE | December 2022 | ||||||||
| Estimated Primary Completion Date | December 2021 (Final data collection date for primary outcome measure) | ||||||||
| Eligibility Criteria ICMJE |
Inclusion Criteria:
Exclusion Criteria: Cohort 1: Toxic causes (drugs, infections) Cohort 2: patients with non-genetic forms of blindness Cohort 3: adult cancer, blood cancer
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| Sex/Gender ICMJE |
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| Ages ICMJE | Child, Adult, Older Adult | ||||||||
| Accepts Healthy Volunteers ICMJE | No | ||||||||
| Contacts ICMJE |
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| Listed Location Countries ICMJE | Germany | ||||||||
| Removed Location Countries | |||||||||
| Administrative Information | |||||||||
| NCT Number ICMJE | NCT03954652 | ||||||||
| Other Study ID Numbers ICMJE | WG-Trio01 | ||||||||
| Has Data Monitoring Committee | No | ||||||||
| U.S. FDA-regulated Product |
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| IPD Sharing Statement ICMJE |
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| Responsible Party | University Hospital Tuebingen | ||||||||
| Study Sponsor ICMJE | University Hospital Tuebingen | ||||||||
| Collaborators ICMJE | Not Provided | ||||||||
| Investigators ICMJE |
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| PRS Account | University Hospital Tuebingen | ||||||||
| Verification Date | November 2020 | ||||||||
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ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |
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