Key Takeaways
- Predictive vs. Diagnostic: Genetic testing identifies both lifetime risks (predictive) and early-stage presence of disease (diagnostic).
- BRCA Impact: Carriers of BRCA1/2 variants face up to an 85% lifetime risk of breast cancer, compared to 15% in the general population.
- Polygenic Risk Scores (PRS): PRS aggregate multiple genetic variants to provide personalized risk profiles for complex conditions like liver disease (MASH).
- Population Screening: Moving beyond family history to population-scale testing can identify over 50% more at-risk individuals and reduce healthcare costs.
Risk and early disease detection
One of the most significant outcomes of genetic sequencing is the ability to detect individuals at increased risk of developing specific conditions (predictive genetic testing), as well as enhancing the ability of healthcare practitioners to identify the presence of disease in its early stages (diagnostic genetic testing).
These tests work by analyzing a sample, typically blood or saliva, for changes in an individual's DNA. Depending on the clinical question, testing may focus on specific genes, use exome sequencing to examine the protein-coding regions of DNA, or employ whole genome sequencing to assess the full genetic code. The approach selected depends on the condition being investigated and the level of detail required.
For example, women who carry specific genetic variants in the BRCA1 and BRCA2 genes are at a significantly increased risk of developing breast or ovarian cancer during their lifetime – up to an 85% lifetime risk in cases of breast cancer and up to a 63% lifetime risk in ovarian cancer. This is a dramatic difference compared to those who do not carry a mutation, who have an overall breast cancer risk of approximately 15%. As a result, a number of countries including Australia, the US, UK, France, Germany and Sweden, offer BRCA1 and BRCA2 testing to people who are born female with a family history of breast or ovarian cancer. This enables early risk detection and the implementation of personalized prevention strategies prior to disease development.
Availability and accessibility of testing vary dramatically between countries, healthcare systems, and regions where factors such as insurance coverage come into play. For example, in Italy BRCA testing isn't free of charge in all regions, and there is significant variation in testing practices across the country.
Another method of assessing disease risk is through the use of polygenic risk scores, a method in genetic research that aggregates the effects of many genetic variants to estimate individual disease risk. Derived from genome-wide association studies (GWAS), PRS aggregate the effects of numerous genetic variants to give an individual an overall “score” to estimate their likelihood of developing a disease. While PRS cannot definitively predict if someone will develop a disease, they provide an estimate of genetic risk. These scores can be integrated with health and lifestyle data to further enhance risk prediction.
The benefits of PRS include early intervention and personalized treatment plans. By identifying individuals at higher genetic risk, clinicians can implement early lifestyle changes and tailor pharmacotherapy to improve treatment outcomes.
However, integrating PRS into clinical practice raises ethical and practical concerns. Patients need to be informed about the limitations of PRS, and genetic counseling is an important part of that process. Data privacy and security are crucial, and equitable access to PRS testing must be ensured. Most polygenic risk scores are currently derived from populations with European ancestry, which limits their accuracy for other ethnic backgrounds.
Genetic counseling plays a critical role in this process. Whether testing is predictive, diagnostic, or part of a research program, patients benefit from professional guidance to understand what results mean, what actions are available, and how findings may affect family members. As genetic testing expands into broader populations and more complex use cases, access to qualified genetic counseling becomes not just helpful but essential for informed decision-making.
PRS offers a meaningful advantage in predicting the risk of developing liver diseases like MASH, particularly when traditional risk factors provide only a general population-level assessment. Unlike traditional risk factors such as obesity and insulin resistance, which offer a general risk assessment, PRS provides a personalized risk profile based on genetic predisposition.
A 2021 study from Biaco et al. examined hepatocellular carcinoma (HCC) risk in individuals with dysmetabolism and non-alcoholic fatty liver disease, now known as metabolic dysfunction-associated steatotic liver disease (MASLD). Researchers developed PRS using genetic variants from genes including PNPLA3, TM6SF2, MBOAT7, and GCKR, and analyzed their impact on HCC development. Using data from the NAFLD cohort and UK Biobank, they found that these PRS could help identify individuals at high risk for HCC, regardless of the presence of significant liver scarring.
PRS represent a meaningful advance in early disease detection and risk stratification. Their successful integration into healthcare depends on addressing ethical, practical, and accessibility challenges, particularly around population representation and informed consent.
Scaling: from family history screening to population testing
Historically, costs and limited access to sequencing technologies have led many genetic screening programs, including those used to identify individuals with risk variants in BRCA genes, to take a family history-based approach. In practice, this means only offering sequencing to individuals with a clear family history of a condition. However, research shows that basing testing on family history alone misses a significant proportion of at-risk patients.
A 2015 cost-effectiveness analysis of population screening for BRCA mutations in Ashkenazi Jewish women living in the UK (who are more likely to carry risk variants than the general population) found that over 50% of carriers in this demographic were missed when using a family history-based approach. The analysis estimated that, based on the available data, a population level BRCA screening could lead to 276 fewer ovarian cancer cases and 508 fewer breast cancer cases if there was a 71% testing uptake. These findings carry direct implications for clinical trial design: if a family history-based approach misses over 50% of carriers in a defined population, enrollment strategies that depend solely on prior diagnosis or referral will face the same structural limitation—artificially constraining the pool of genetically eligible participants before screening even begins.
As targeted treatments and interventions continue to advance, integrating genetic testing into routine healthcare becomes increasingly important for connecting patients with therapies matched to their genetic profile.
This has direct implications for clinical research. As more trials require genetic confirmation for eligibility, the ability to identify, test, and engage patients at a population level is no longer a public health aspiration alone. It is a practical requirement for executing precision medicine programs effectively. Sponsors and clinical teams designing genetically stratified trials must consider not only how patients are recruited, but how genetic testing is delivered, explained, and scaled across diverse populations and geographies.
For more information, download our whitepaper on genetic testing as a public health initiative.