Background
With more than 50% of all rare disease patients remaining without a firm diagnosis after short-read exome or genome sequencing (SR-GS), ‘solving the unsolved’ genetic diseases is one of the most important tasks in human genetics today. Reasons for missed diagnoses include technological shortcomings in genomic variation detection and lack of large cohorts for efficient prioritization of disease-causal variants. Long-read genome sequencing (LR-GS) is expected to enhance diagnostic precision for complex genomic variation, potentially narrowing this diagnostic gap.
Dedicated to the evaluation of novel concepts of care, the members of this consortium are based on preexisting centers of rare diseases with multidisciplinary teams in Germany. Involved partners have already successfully implemented advanced diagnostic approaches, combined with comprehensive phenotypic characterization, into routine clinical practice (e.g. within Translate-NAMSE). Those established patient care pathways have subsequently been sustained through reimbursement by several German health insurers. The National Strategy for Genomic Medicine (genomDE) and 'Modellvorhaben Genomsequenzierung' (§64e SGB V) provide the legal and regulatory framework for the broad implementation of clinical genome sequencing for rare disease and cancer patients.
Objectives
This study aims to introduce LR-GS into healthcare systems, demonstrating its diagnostic value and sustainability in clinical practice. By leveraging on a multi-center approach and collaboration with national and European research environments, the project seeks to pave the way for widespread adoption of LR-GS technology in routine healthcare, potentially benefiting a substantial number of individuals with unresolved genetic disorders.
Study outline
In order to demonstrate the advantage of untargeted LR-GS compared to SR-GS to establish firm genetic diagnoses, we will rely on a cohort of unsolved patients with neurological, neurodevelopmental, and imprinting disorders that is expectedly enriched for complex genomic variation. The cohort will be mainly recruited from clinical expert centers ensuring standardized in-depths phenotyping and translation of novel findings into clinical management of the patients and their families. Within the framework of genomDE, we will then implement 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.
Impact
We strongly believe that this project has the potential to substantially advance the implementation of the LR-GS in routine care across Germany. In contrast to focused research projects, reimbursement by the health insurance system opens the door to implement this technology on a larger scale. While the current pilot study involves only 4 sequencing centers, the project's organizational framework and integration into the national healthcare system are specifically designed for a nationwide expansion. Presently, approximately 4,000 index cases undergo annual investigation using SR-GS across these centers. It is estimated that from the 20 designated sites within the genomeDE project, about 20.000 index cases will annually be investigated. Despite the high number, this forms only a fraction of the about 1.5 million patients in Germany who have not yet received a molecular diagnosis and who could benefit from an extended genome analysis.