Identification of novel disease-causing structural variants by optical genome mapping and long-read whole genome sequencing

• Applicants: Professorin Dr. Christine Klein; Professorin Dr. Katja Lohmann
• Subject Area: Human Genetics ; Molecular and Cellular Neurology and Neuropathology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 575669435

Identifying causative genetic variants in patients and families with a monogenic disease is highly significant in establishing a definitive diagnosis with implications for treatment and counseling. Genetic causes can be manifold, and structural variants (SV), such as copy number variants (CNV), inversions, and repeat expansions, are increasingly recognized as contributing to genetic disorders but are often challenging to detect. The diagnostic yield in several neurological disorders, including ataxia and dystonia, is <50%, which is unsatisfactory. It is expected that SV explain a significant portion of the yet unsolved genetic basis, including novel repeat expansions in ataxia patients and a broad spectrum of SV in dystonia. Notably, the testing in isolated populations or populations that have not yet been intensively studied in genetic research, so-called underrepresented populations (URP), may facilitate the identification of new disease genes. We here propose to use two up-to-date methods to screen patients from Europe and URPs with rare neurological disorders, with a focus on ataxia and dystonia, for SV by optical genome mapping (OGM, Saphyr® system, Bionano Genomics) and long-read genome sequencing (LR-WGS, PrometION, Oxford Nanopore). While OGM is an emerging next-generation cytogenetic technique that uses ultra-high molecular weight DNA to evaluate the fluorescent-labeled pattern of individual DNA molecules, LR-WGS is based on third-generation sequencing of very long DNA fragments, both allowing the detection of SV. By using OGM, we want to overcome the limitations of sequencing-based approaches, including difficulties targeting GC-rich and complex genomic regions. Further, OGM screens for SV genome-wide at significantly lower costs compared to LR-WGS. We are experienced in clinical and genetic studies and have already successfully used OGM to solve selected patients. We here propose a project with a three-step procedure to detect SV in novel disease genes in ataxia or dystonia, by (1) screening of patients using OGM and/or LR-WGS, (2) validating newly identified candidate SV in available family members and a larger group of up to 1000 patients and 500 controls, and (3) gaining first insights into altered gene function by testing for expressional changes resulting from these variants. We aim to screen 100 carefully selected index patients from multiplex families and/or with an early onset. About half of these patients have already been collected, while the remaining patients are being recruited in Lübeck and from URP in Argentina, Chile, and Malaysia. The discovery of novel SV will help end the diagnostic odyssey for affected individuals and provide novel candidate genes also for other patients. It offers novel global insights into disease mechanisms and promotes further research with the ultimate goal of developing new therapies.

• DFG Programme: Research Grants