Clinical trial NCT03954652: Whole Genome Trio Sequencing as a Standard Routine Test in Patients With Rare Diseases - "GENOME FIRST APPROACH"
Official title: Whole Genome Trio Sequencing as a Standard Routine Test in Patients With Rare Diseases - "GENOME FIRST APPROACH"
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Rare Diseases
Genetic Predisposition
Keywords: Rare Diseases
Genetic Predisposition
Whole-exome sequencing
WGS-trio analysis
Whole Genome Sequencing (WGS)
Lead sponsor: University Hospital Tuebingen
Sponsor class: OTHER
First posted: 2019-05-17
Enrollment: 1350
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
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

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:

* 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.

Eligibility 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-

Primary outcomes:
measure: Full genomic sequence analysis carried out by Whole Genome Sequencing (WGS)
timeFrame: Day 1
Secondary outcomes:
measure: Genome sequencing
timeFrame: Day 1
measure: De novo alterations
timeFrame: Day 1
Other outcomes:
Locations:
city: Tübingen
country: Germany
facility: University Hospital Tübingen
Study officials:
affiliation: University Hospital Tübingen
name: Olaf Riess, Prof. Dr.
role: STUDY_DIRECTOR
References: