Initiative for Clinical Long-read Sequencing (IonGER)

Initiative for Clinical Long-read Sequencing - Towards Implementation of Long-read Genome Sequencing in Routine Diagnostics

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Genetic Predisposition
• Intervention / Treatment: Genetic: Next-Generation Sequencing (NGS)

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.

• Study Type: Interventional
• Enrollment (Estimated): 500
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Tobias Haack, Dr.; Phone Number: 77696 +49 7071 29; Email: tobias.haack@med.uni-tuebingen.de
• Study Contact Backup: Name: Olaf Rieß, Prof. Dr.; Phone Number: 72288 +49 7071 29; Email: olaf.riess@med.uni-tuebingen.de

Study Locations

• Germany
  • Tübingen, Germany, 72076
    • University Hospital Tübingen
    • Contact: Tobias Haack, Dr.; Phone Number: 77696 +49 7071 29; Email: tobias.haack@med.uni-tuebingen.de
    • Contact: Rieß, Prof. Dr.; Phone Number: 72288 +49 7071 29; Email: olaf.riess@med.uni-tuebingen.de

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Retrospective cohort; Subjects with unclear molecular cause of the disease. The subjects are clinically characterized in the context of outpatient/ inpatient standard care at the University Hospital Tübingen (UKT) or cooperating locations.	Genetic: Next-Generation Sequencing (NGS); Sequencing of genomes (Long read NGS)
Experimental: Prospective cohort; Subjects with indication for genome diagnostics (e.g. within the initiative for genomic medicine (genomDE) based on §64e German Social Code (SGB) Fifth Book (V) (SGB V).	Genetic: Next-Generation Sequencing (NGS); Sequencing of genomes (Long read NGS)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	A molecular diagnosis is considered confirmed when likely pathogenic or pathogenic variants are identified according to the American College of Medical Genetics and Genomics (ACMG). classification.	Day 1

Collaborators and Investigators

• Sponsor: University Hospital Tuebingen
• Collaborators: Charite University, Berlin, Germany; RWTH Aachen University; Medical University of Hannover
• Investigators: Principal Investigator: Tobias Haack, Dr. med., University Hospital Tübingen

Study record dates

Study Major Dates

• Study Start (Estimated): December 1, 2023
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: September 13, 2023
• First Submitted That Met QC Criteria: September 22, 2023
• First Posted (Actual): September 29, 2023

Study Record Updates

• Last Update Posted (Actual): September 29, 2023
• Last Update Submitted That Met QC Criteria: September 22, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Rare diseases; Long-read sequencing; Cancer preposition; Translate-NAMSE; German initiative for genomic medicine (genomDE)
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Disease Susceptibility; Genetic Predisposition to Disease
• Other Study ID Numbers: IonGER

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The IonGER study will provide data in a pseudonymised manner to national and international databases set up to increase the diagnostic yield through advanced analysis tools and matchmaking against other cohorts
• IPD Sharing Time Frame: Data will become available after analysis and unlimited.
• IPD Sharing Supporting Information Type: ANALYTIC_CODE

Drug and device information, study documents

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