Clinical trial NCT06060184: Initiative for Clinical Long-read Sequencing
Official title: Initiative for Clinical Long-read Sequencing - Towards Implementation of Long-read Genome Sequencing in Routine Diagnostics
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: NA
Conditions: Genetic Predisposition
Keywords: Long-read sequencing
Rare diseases
Cancer preposition
Translate-NAMSE
German initiative for genomic medicine (genomDE)
Lead sponsor: University Hospital Tuebingen
Sponsor class: OTHER
Collaborators: name: RWTH Aachen University
name: Medical University of Hannover
name: Charite University, Berlin, Germany
First posted: 2023-09-29
Enrollment: 500
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Parallel Assignment
Primary purpose: DIAGNOSTIC

Brief summary: The study aims to comprehensively introduce Long-read Genome sequencing (LR-GS) based genetic testing into clinical routine. In order to demonstrate the superiority of untargeted LR-GS over Short-read Genome sequencing (SR-GS) to establish firm genetic diagnoses, the investigators will rely on a multi-center "Translate Nationale Aktionsbündnis für Menschen mit Seltenen Erkrankungen" (Translate National Action Alliance for People with Rare Diseases Germany, TNAMSE) cohort of unsolved patients with neurological, neurodevelopmental, and imprinting disorders that is expectedly enriched for complex genomic variation. Within the framework of genomDE, the investigators will then implement, for the first time, LR-GS in the diagnostic work-up of a prospective cohort of patients with a broad range of clinical indications including rare diseases and cancer predisposition.

Detailed description: The proposed study aims to develop a blueprint for the implementation of LR-GS in clinical diagnostics. Hence Standard Operating Procedures (SOPs) and guidelines for library preparation, bioinformatic analysis, and clinical interpretation will be compiled. Furthermore, the investigators intend to develop an open source 'gold standard' bioinformatics pipeline, addressing all relevant types of genomic alterations, thus providing the bioinformatic basis for a streamlined implementation of LR-GS at other sites. In addition to in-depth phenotype information the availability of SR-GS will be instrumental to benchmark the ability to detect different types of genomic variation. Additional relevant issues for genetic testing such as variant calling in difficult-to-map genomic regions, detection of genomic methylation patterns, characterization of repeat expansion and duplicated genes, and haplotype-phased genome de novo assembly will be addressed. Moreover, based on the strong background in Artificial Intelligence (AI) driven variant prioritization in the consortium, the investigators aim to implement and/or develop tools that enable an efficient prioritization of disease-causing variants. Beyond the usage within the context of the proposed study, generated datasets will be made available according to the Findable, Accessible, Interoperable and Reusable (FAIR) principles for national (German Human Genome-Phenome Archive, GHGA) and international (European Genome-Phenome Archive, EGA, Genome-Phenome Analysis Platform, GPaP) data repositories. the investigators aim to establish a population scale reference dataset for Structural variants (SV), which is absolutely mandatory in the context of rare disease diagnostics.

Eligibility criteria: Inclusion Criteria:

* Unclear molecular cause of the disease (retrospective cohort)
* Indication for genome diagnostics (prospective cohort; e.g. within the initiative for genomic medicine (genomDE) based on §64e SGB V)
* Suspected genetic cause of the disease

Exclusion Criteria:

- Missing informed consent of the patient or legal guardian

Primary outcomes:
measure: Number of patients with Rare Disease (RD) or cancer predisposition syndromes with confirmed diagnosis by LR-GS compared to previous diagnostic methods including SR-GS
timeFrame: Day 1
Secondary outcomes:
Other outcomes:
Locations:
city: Tübingen
country: Germany
facility: University Hospital Tübingen
Study officials:
affiliation: University Hospital Tübingen
name: Tobias Haack, Dr. med.
role: PRINCIPAL_INVESTIGATOR
References: