Abstract
Genetic diagnostics is driven by technological advances, forming a tight interface between research, clinic and industry, which enables rapid implementation of new technologies. Short-read genome and exome sequencing, the current state of the art in clinical genetics, can detect a broad spectrum of genetic variants across the genome. However, despite these advancements, more than half of individuals with rare diseases remain undiagnosed after genomic investigations. Long-read whole-genome sequencing (LR-WGS) is a promising technology that identifies previously difficult-to-detect variants while also enabling phasing and methylation analysis and has the potential of generating complete personal assemblies. To pave the way for clinical use of LR-WGS, the clinical genomic community must establish standardized protocols and quality parameters while also developing innovative tools for data analysis and interpretation. In this Perspective, we explore the key challenges and benefits in integrating LR-WGS into routine clinical diagnostics.
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Acknowledgements
A.L. was supported by grants from the Swedish Research Council (2019-02078), Region Stockholm (FoUI-1000468 and FoUI-978581), the Rare Diseases Research Foundation (Sällsyntafonden), the Swedish Brain Foundation (FO2024-0128-HK-44) and the Swedish Cancer Society (24 3504 Pj).
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Conceptualization: J.E. and A.L.; writing of manuscript: J.E., M.E., M.N. and A.L.; figures: J.E., A.L. and M.E.
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Eisfeldt, J., Ek, M., Nordenskjöld, M. et al. Toward clinical long-read genome sequencing for rare diseases. Nat Genet (2025). https://doi.org/10.1038/s41588-025-02160-y
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DOI: https://doi.org/10.1038/s41588-025-02160-y
