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Population genetic screening efficiently identifies carriers of autosomal dominant diseases
J J Grzymski1,2, G Elhanan3, J A Morales Rosado4,5
1Renown Health, Reno, NV, USA. joe.grzymski@dri.edu.
Insights
Population genetic screening effectively identified carriers of high-risk hereditary breast and ovarian cancer (HBOC), Lynch syndrome (LS), and familial hypercholesterolemia (FH). Most identified carriers were previously unknown, highlighting gaps in traditional risk assessment.
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.
Abstract:
Three inherited autosomal dominant conditions-BRCA-related hereditary breast and ovarian cancer (HBOC), Lynch syndrome (LS) and familial hypercholesterolemia (FH)-have been termed the Centers for Disease Control and Prevention Tier 1 (CDCT1) genetic conditions, for which early identification and intervention have a meaningful potential for clinical actionability and a positive impact on public health1. In typical medical practice, genetic testing for these conditions is based on personal or family history, ethnic background or other demographic characteristics2. In this study of a cohort of 26,906 participants in the Healthy Nevada Project (HNP), we first evaluated whether population screening could efficiently identify carriers of these genetic conditions and, second, we evaluated the impact of genetic risk on health outcomes for these participants. We found a 1.33% combined carrier rate for pathogenic and likely pathogenic (P/LP) genetic variants for HBOC, LS and FH. Of these carriers, 21.9% of participants had clinically relevant disease, among whom 70% had been diagnosed with relevant disease before age 65. Moreover, 90% of the risk carriers had not been previously identified, and less than 19.8% of these had documentation in their medical records of inherited genetic disease risk, including family history. In a direct follow-up survey with all carriers, only 25.2% of individuals reported a family history of relevant disease. Our experience with the HNP suggests that genetic screening in patients could identify at-risk carriers, who would not be otherwise identified in routine care.
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