A national ecosystem for long-read genome sequencing: Integrating population genomics and rare disease diagnostics in Sweden

Abstract

To evaluate the clinical implementation of long-read genome sequencing (lrGS) and establish the population reference resources needed to support its use in diagnostics, we integrate two complementary initiatives: Genome of Sweden (GoS), Swedens contribution to Genome of Europe (GoE), and the Genomic Medicine Sweden - Rare Diseases (GMS-RD) long-read sequencing pilot. The initial GoS release of 576 individuals provides population-scale maps of genetic and epigenetic variation. Among 485 GMS-RD probands, 161 (33.2%) receive a molecular diagnosis, with lrGS providing added clinical value in 40 (24.8%). As a first-line test, lrGS could have avoided at least 42 follow-up analyses and an additional testing cycle in 7.2% of probands, reducing costs and the burden on patients. By integrating population and clinical long-read genomics, Sweden establishes a national ecosystem for genomic research and clinical diagnostics. Our findings support the clinical implementation of lrGS and offer a scalable model for national collaboration.