Whole Genome Trio Sequencing as a Standard Routine Test in Patients With Rare Diseases - "GENOME FIRST APPROACH"

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).

Study Overview

• Status: Completed
• Conditions: Rare Diseases; Genetic Predisposition
• Intervention / Treatment: Genetic: WGS-Diagnostic

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 Type: Interventional
• Enrollment (Actual): 1350
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Germany
  • Tübingen, Germany, 72076
    • University Hospital Tübingen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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-

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: 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.
Other: 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.
Other: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Full genomic sequence analysis carried out by Whole Genome Sequencing (WGS)	Number of genomic variants in disease and health parents by WGS (a Next-Generation Sequencing Technology, NGS)	Day 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Genome sequencing	Verification of the genetic causes of unclear genetic diseases by clinical genome sequencing	Day 1
De novo alterations	Number of de novo alterations in genome of the enrolled population	Day 1

Collaborators and Investigators

• Sponsor: University Hospital Tuebingen

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2019
• Primary Completion (Actual): October 1, 2022
• Study Completion (Actual): October 1, 2022

Study Registration Dates

• First Submitted: May 9, 2019
• First Submitted That Met QC Criteria: May 16, 2019
• First Posted (Actual): May 17, 2019

Study Record Updates

• Last Update Posted (Actual): October 18, 2022
• Last Update Submitted That Met QC Criteria: October 17, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: Rare Diseases; Genetic Predisposition; Whole Genome Sequencing (WGS); WGS-trio analysis; Whole-exome sequencing
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Disease Susceptibility; Genetic Predisposition to Disease; Rare Diseases
• Other Study ID Numbers: WG-Trio01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No