Genomic Screening and Actionable Genetic Conditions

Introduction to Population Genomic Screening

Population screening for disease-causing genetic variants is a modern approach to identifying individuals at risk for preventable diseases, such as certain cancers and heart disease. This method can uncover genetic risks in individuals who may not have a personal or family history that would otherwise prompt clinical attention.

• Genomic screening involves analyzing DNA for pathogenic or likely pathogenic variants in genes associated with disease.

• Actionable genetic conditions are those for which interventions can reduce morbidity and mortality.

• Three key conditions with tier 1 evidence for intervention are: Hereditary Breast and Ovarian Cancer (HBOC) syndrome, Lynch syndrome, and Familial Hypercholesterolemia (FH).

• Genes involved: - HBOC: BRCA1, BRCA2 - Lynch syndrome: MLH1, MSH2, MSH6, PMS2 - FH: LDLR, APOB, PCSK9

Example: Screening for BRCA1/2 variants can identify individuals at risk for breast and ovarian cancer, even if they lack a family history.

Study Design and Methods

Observational Study of Genomic Screening Outcomes

This study evaluated the impact of genomic screening in an unselected population using electronic health records (EHR) from the Geisinger MyCode Community Health Initiative.

• Participants were not selected based on disease risk.

• Exome sequencing was used to identify pathogenic/likely pathogenic variants.

• Variants were filtered and confirmed in a CLIA-certified laboratory.

• Results were disclosed to participants and their primary care clinicians, followed by genetic counseling and risk management recommendations.

• Risk management guidelines were personalized based on disease status.

Definitions: - Pathogenic variant: A genetic change known to cause disease. - Likely pathogenic variant: A genetic change strongly suspected to cause disease. - CLIA-certified laboratory: A lab meeting federal standards for clinical testing.

Clinical Outcomes of Genomic Screening

Identification of At-Risk Individuals

Genomic screening identified individuals with actionable genetic variants who were previously unaware of their risk status.

• 87% of participants (305/351) did not have a prior genetic diagnosis.

• 65% had EHR evidence of relevant personal and/or family history of disease.

• None of the FH or Lynch syndrome variant carriers had a prior clinical diagnosis.

Risk Management and Early Detection

Post-disclosure, many participants underwent recommended risk management procedures, and some received new clinical diagnoses.

• 70% of eligible individuals (179/255) had a recommended risk management procedure after results disclosure.

• 13% (41/305) received a relevant clinical diagnosis post-disclosure.

• Procedures included breast MRI, colonoscopy, lipid panel, and risk-reducing surgeries.

Example: Among HBOC carriers, early-stage cancers were diagnosed post-disclosure, facilitating early intervention.

Demographic and Health Characteristics

Participant Demographics

Study participants were predominantly of European ancestry, older, and had higher comorbidity indices compared to the general patient population.

• 54% female, 99% European ancestry, median age 63 years.

• Higher comorbidity index than MyCode and Geisinger patients overall.

Tables: Key Data Summaries

Table 1: Demographic and Health Characteristics

Table 2: Risk Management and Postdisclosure Diagnoses

Table 3: Types of Postdisclosure Risk Management

Table 4: Factors Associated with Postdisclosure Risk Management

Implications and Recommendations

Clinical Utility and Future Directions

Genomic screening programs can identify individuals at increased genetic risk and facilitate risk management and early disease detection. The study highlights the need for further research to optimize screening strategies, address limitations in EHR data, and ensure benefits outweigh risks.

• Early detection of disease can improve outcomes, but longer-term studies are needed to assess clinical utility.

• Genetic counseling is associated with increased adherence to risk management recommendations.

• Screening for FH may be most beneficial if started in childhood; screening for hereditary cancers may be more appropriate at later ages.

• Future studies should include diverse populations and patient-reported outcomes.

Additional info: The study used rigorous variant classification and confirmation processes to ensure accuracy of genetic findings. The classic World Health Organization principles for screening have been updated for genomic technologies, emphasizing the need for evidence-based implementation.