Population genetic screening efficiently identifies carriers of autosomal dominant diseases

Area of Science:

• Genetics
• Public Health
• Preventive Medicine

Background:

• Three autosomal dominant conditions—BRCA-related hereditary breast and ovarian cancer (HBOC), Lynch syndrome (LS), and familial hypercholesterolemia (FH)—are designated Centers for Disease Control and Prevention Tier 1 (CDCT1) genetic conditions.
• Early identification and intervention for CDCT1 conditions offer significant clinical actionability and public health benefits.
• Current genetic testing relies on personal/family history, ethnicity, or demographics, potentially missing many at-risk individuals.

Purpose of the Study:

• To evaluate the efficiency of population screening in identifying carriers of HBOC, LS, and FH genetic variants.
• To assess the impact of identified genetic risk on health outcomes within a large cohort.

Main Methods:

• Analysis of a cohort of 26,906 participants from the Healthy Nevada Project (HNP).
• Evaluation of carrier rates for pathogenic/likely pathogenic (P/LP) variants in HBOC, LS, and FH.
• Assessment of clinical relevance, prior diagnoses, and medical record documentation of genetic risk among carriers.
• Follow-up survey to ascertain reported family history among identified carriers.

Main Results:

• A combined carrier rate of 1.33% for P/LP variants in HBOC, LS, and FH was observed.
• Among carriers, 21.9% had clinically relevant disease, with 70% diagnosed before age 65.
• A significant majority (90%) of at-risk carriers were previously unidentified.
• Less than 19.8% of carriers had documented inherited genetic disease risk, and only 25.2% reported a relevant family history.

Conclusions:

• Population-based genetic screening can efficiently identify carriers of significant inherited conditions like HBOC, LS, and FH.
• Routine clinical care and traditional risk assessment methods frequently miss individuals with substantial genetic risk.
• Widespread genetic screening holds potential for earlier detection and intervention, improving public health outcomes.