Population Screening for Rare Pathogenic Variants as the Low Hanging Fruit for Public Health Genomics Across the Lifespan

Posted on by Muin J. Khoury, Office of Genomics and Precision Public Health, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia

a family with a tree of DNA with low hanging circles of people and many different hands reaching to themRapid advances in human genome sequencing technologies have accelerated the integration of genomics into clinical practice. Genomics has demonstrated clinical utility as a diagnostic tool for certain diseases, but its potential for population screening is still work in progress. In principle, DNA-based population screening can identify persons with rare pathogenic variants who are at high risk of preventable diseases and disabilities and could benefit from early interventions. In addition, population genomic screening for common variants could help provide risk assessment and prevention for common diseases for persons with high polygenic risks, to identify carriers for certain genetic conditions for reproductive planning, and to identify persons with certain pharmacogenomic traits to guide the use of medications across the lifespan. Since we all have genetic variation at multiple genes, genomic screening could impact large swaths of the population.

Join us on May 18 during public health genetics and genomics week for our webinar: We screen newborns, don’t we? Progress in DNA-based population screening.

Nevertheless, before DNA-based population screening can be implemented, rigorous evaluation of the validity and utility for different intended uses needs to be conducted and multiple questions answered regarding ethical, legal, social, financial and implementation issues. These topics have been addressed by multiple authors and summarized in previous blog posts.

Why Focus on Rare Pathogenic Variants in Population Screening?

Newborn screening is a highly successful public health program that has led to major improvements in outcomes for a variety of mostly rare genetic diseases associated with preventable long-term disease, disability, and death. In the United States, newborn screening identifies >13 000 each year who require early intervention and lifelong care. Newborn screening relies primarily on biochemical, physiological, and other tests and not DNA-based analysis, although genome sequencing is currently being actively studied as an adjunct to other testing modalities.

Using the rationale of newborn screening for rare disorders for which a specific combination of features pertain (serious outcome, effective prevention of diseases and disabilities, asymptomatic latent period, and an affordable assay), James Evans and coauthors proposed in 2013 that DNA-based population screening for rare pathogenic variants could be an early low hanging fruit for the emerging field of public health genomics. They called for a new partnership to be forged between the genomics and public health communities. The partnership would expand the focus from solely common diseases to identify those rare but, in aggregate, affecting 1-2% of persons in the population. This effort would use increasingly affordable sequencing technology to measure a defined set of genes that meet the evidentiary bars of high disease risk and effective intervention.

Genes mentioned in the context of population genomic screening are included in our CDC tier 1 genomic applications database. These include high-risk cancer susceptibility genes, such as BRCA1, BRCA2 and PALB2 for hereditary breast and ovarian cancerMLH1MSH2 and MSH6 for Lynch syndrome, and genes for cholesterol metabolism (LDLRAPOB and PCSK9) for familial hypercholesterolemia. For persons identified to be at high genetic risk of these conditions, there are evidence-based guidelines for effective risk management interventions to prevent disease.

How About Using Polygenic Risk Scores in Population Screening?

In the past decade, there has been growing interest in using polygenic risk scores (PRS) in medicine and public health. PRS calculate the additive influence of many common genetic variants on the risk of a particular disease. The increasing popularity of PRS is likely owing to low cost, improved accessibility, and potential to generate risk estimates on large populations.

PRS are typically calculated using genotyping array and sequencing technologies. They have been proposed as a possible alternative for population screening to identify individuals at high risk. However, such an approach would miss carriers of rare pathogenic variants that are measured using sequencing technologies.

In a recent paper, Lacaze and coauthors argued that while population genomic screening to detect rare genetic variants for medically actionable conditions is increasingly supported by evidence of clinical utility, much less evidence supports screening for polygenic risk scores, which do not detect rare variants. They further posit that using only polygenic scores in population screening initiatives, while ignoring the detection of higher-risk rare genetic variants, is ill-advised.

Indeed, the field of PRS, while promising, is very much work in progress. Validation of predictive PRS models, including defining absolute risk thresholds for effective clinical interventions, is still lacking for most disease states and requires integration with other risk factors into disease risk models. Reporting of PRS is not yet standardized for most diseases and is not yet aligned with existing clinical guidelines. In addition, PRS are subject to ancestry-specific biases.

Moving Forward

A decade after the publication of the article by Evans et al, many studies have been conducted to assess the validity and utility of DNA-based screening in multiple populations, age groups and settings. Our online knowledge base can be searched for the latest publications. A recent study identified 12 population-based genomic screening programs in the United States and described their implementation logistics and potential health impacts. More recently, Laura Milko and I co-edited a collection of articles on DNA-based population screening. These articles provide a mix of studies on various types of population screening, as well as commentaries on various scientific, technical, implementation as well as ethical, legal and social aspects of genomic screening.  Our blog posts have tackled various aspects of this important and evolving topic. We will continue to track progress in this important field.

Join us for our May 18 webinar to discuss progress in population genomic screening. In the meantime, we are interested in hearing your input on the impact and pitfalls of population genomic screening as a tool for public health.

Please submit your comments below.

Posted on by Muin J. Khoury, Office of Genomics and Precision Public Health, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GeorgiaTags

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Page last reviewed: February 27, 2023
Page last updated: February 27, 2023