Long-read Genome Sequencing: Transforming Genetic Diagnostics for Rare Diseases
Despite rapid advances in genome and exome sequencing, many individuals with rare diseases remain undiagnosed. In a Perspective article published in Nature Genetics, researchers at Karolinska Institutet highlight how long-read whole genome sequencing, LR-WGS, offers a paradigm shift in genetic testing.
Allowing for the detection of previously unrevealed genetic variants, such as complex structural rearrangements, repetitive sequences, as well as epigenetic alterations, offering a more complete picture of the genome.
“With long-read sequencing, we can now access parts of the genome that were previously invisible - complex variants and structural changes that we know play a crucial role in rare diseases”, says lead author Jesper Eisfeldt, the Department of Molecular Medicine and Surgery.
In the article describes the Swedish national efforts bringing LR-WGS into clinical practice. Hundreds of individuals have already been analyzed though the Genomic Medicine Sweden initiative, and a prospective study of 1,000 individuals with neurological conditions is underway. LR-WGS has shown promise in increasing diagnostic yields and could eventually replace multiple standard genetic tests with a single, comprehensive assay.
“We envision a future where long-read sequencing replaces the full spectrum of genetic tests currently used in clinical diagnostics today”, says corresponding author, ProfessorAnna Lindstrand.
The authors are supported by the Swedish Research Council, Region Stockholm, the Swedish Brain Foundation, the Swedish Cancer Society, and the Rare Diseases Research Foundation.
Publication
Toward clinical long-read genome sequencing for rare diseases Jesper Eisfeldt, Marlene Ek, Magnus Nordenskjöld, Anna Lindstrand. Nature Genetics 2025 May. doi:10.1038/s41588-025-02160-y