Genome sequencing is now a core part of rare disease diagnostics in several healthcare systems. However, the path from sequencing technology to clinical impact still depends on infrastructure, interpretation, and coordinated healthcare delivery.
In last week’s episode of The Genetics Podcast, we hosted Dr. Anna Lindstrand, Professor and Consultant in Clinical Genetics and Genomics at the Karolinska Institute, Director of the Clinical Genetics diagnostic laboratory, and group leader for the Rare Diseases research group. She discusses how Sweden has implemented clinical genome sequencing, what long-read sequencing adds to diagnostics, and how national genomics programs can accelerate translation. Her perspective reflects more than a decade of clinical implementation and national collaboration through Genomic Medicine Sweden.
At Karolinska, whole genome sequencing (WGS) has become the default diagnostic test for many rare disease patients. The program began in 2015 and has steadily scaled. Anna explained that genome sequencing is now the first line test for most rare disease referrals.
Referrals typically come from other clinical specialties that send a patient sample and clinical information to the clinical genetics lab. The genome is sequenced and interpreted using national analysis pipelines developed through Genomic Medicine Sweden.
In cancer diagnostics, the approach differs. Many tumors are still tested using targeted gene panels, particularly in hematology and solid tumor diagnostics. However, whole genome sequencing has already become a first line test in some contexts, including childhood cancers in Sweden.
This tiered approach reflects how different sequencing technologies are currently used in clinical workflows.
Short-read sequencing enabled large scale clinical genomics programs. However, some parts of the genome remain difficult to resolve.
Long-read sequencing offers clearer insight into structural variants, repeat expansions, and complex genomic regions.
Anna described how the field often compares the two approaches.
“People compare it to taking your encyclopedia of 46 books and shredding them and then piecing them back together.”
Long-reads reduce that fragmentation, enabling more direct interpretation of genomic structure.
In a study on children with neurological disease, Anna’s group compared short-read and long-read sequencing. They observed clear additional value in about 15% of cases. The main benefits came from improved detection and interpretation of structural variants and repeat expansions.
However, long-read sequencing is not yet a routine first line clinical test. Infrastructure, cost, and analytical pipelines still limit large scale adoption. Clinical implementation studies are now focused on determining where long reads add the most value.
Genome sequencing does not always provide a definitive diagnosis. In those cases, additional functional assays can help interpret variants. RNA sequencing is already used clinically in some situations to confirm splicing defects or clarify uncertain variants.
Anna noted that RNA data can reveal pathogenic signals that are difficult to detect from DNA alone. RNA sequencing is particularly helpful for identifying splicing changes or confirming the functional impact of candidate variants.
Other multi-omic approaches are still emerging in diagnostics. Proteomics, for example, remains largely in the research stage for rare disease diagnostics.
Methylation analysis may become an important next layer of genomic interpretation. Epigenetic signatures linked to certain disorders can act as functional evidence supporting the pathogenicity of genetic variants.
One of the defining features of Sweden’s genomics strategy is national coordination. Genomic Medicine Sweden was created as a collaboration between clinical genetics centers across the country. The goal is to harmonize genomic diagnostics and ensure that patients receive the same testing regardless of location.
Sweden’s healthcare system is regionally organized, which can create variation in access to advanced diagnostics. The national program helps address this by coordinating infrastructure, analysis pipelines, and expertise.
The collaboration has produced a shared rare disease analysis pipeline and a national multicenter study designed to explore new genomic technologies in unresolved cases.
A national genomics platform is also being built to store and analyze genomic data from clinical sequencing programs. With patient consent, these data can support research and help identify patients eligible for clinical trials.
If genomic and clinical data can be queried in a coordinated way, health systems are better positioned to identify genetically eligible patients, assess feasibility for rare disease studies, and support more efficient site selection and recruitment.
Genomic medicine is increasingly linked to targeted therapies. That shift is forcing changes in how clinical genetic findings are interpreted and reported. Traditional clinical genetics has focused on highly validated variants with clear implications for family testing and reproductive decisions.
Precision medicine introduces new scenarios where genetic findings may guide treatment even if the evidence is still emerging. Anna explained that this will require updated reporting frameworks beyond existing standards.
This change will affect how variants are interpreted, shared, and incorporated into clinical decision making. For drug developers, this shift matters because genomic testing is increasingly being used not only to end a diagnostic odyssey, but also to identify patients for targeted therapies and genotype-specific trials. That raises new questions about what level of evidence is sufficient when the immediate goal is treatment selection or trial eligibility.
Another emerging question is how genomics should be used for prevention. Today, many individuals are tested only after symptoms appear or after a relative receives a diagnosis. Anna suggested that broader adult genomic screening may become part of future healthcare systems.
For example, individuals could be tested in early adulthood for high penetrance risk variants. This approach could identify risk before disease develops and enable earlier intervention.
Pharmacogenomics may also drive adoption of preventive genomics. If genomic testing can help physicians select safer or more effective medications, the health economic benefits may be immediate.
Several areas will shape the next phase of genomic medicine. Long-read sequencing will likely improve structural variant detection and enable more complete genome interpretation. Multi-omic assays such as RNA sequencing and methylation profiling may become routine tools for interpreting difficult cases.
National genomic data infrastructure will also play a major role. Large clinical genomic datasets can help identify patients for clinical trials and accelerate the discovery of new disease mechanisms.
Anna’s research continues to focus on structural variation and complex genome architecture. Advances in reference genomes, long-read sequencing, and pan genome projects are opening new parts of the genome that were previously difficult to study. Understanding these regions may reveal new mechanisms of rare disease and improve diagnostic yield.
Listen to the full episode below.