Population Genomic Screening Efforts May Identify High-Risk Individuals Before Disease Onset

According to researchers, these observations suggest a potential need to modify the current framework for clinical risk disclosure.

A study published in JAMA Network Open suggested that approximately 1% of the middle-aged adult population in the UK Biobank harbored a pathogenic variant associated with familial hypercholesterolemia, hereditary breast or ovarian cancer syndrome, or Lynch syndrome. 

According to researchers, these individuals were at increased risk of disease, and carrier status was not reliably detected based on family history.

“Population genomic screening efforts may enable identification of these high-risk individuals before disease onset so that established risk mitigation strategies to overcome inherited disease susceptibility can be implemented,” the authors wrote. 

In this cohort study, researchers used gene-sequencing data from 49,738 participants in the UK Biobank who were recruited from 22 sites across the UK. Family history of disease in parents and siblings was reported by the participants using a structured assessment tool at the time of enrollment. Additionally, at the time of their initial study visit, participants completed questionnaires about health history and lifestyle and underwent physical assessment and phlebotomy. 

Of the overall cohort, 441 (0.9%) harbored a pathogenic or likely pathogenic variant associated with any of 3 genomic conditions, including 131 (0.3%) for familial hypercholesterolemia, 235 (0.5%) for hereditary breast and ovarian cancer syndrome, and 76 (0.2%) for Lynch syndrome. Moreover, the presence of these variants was found to be associated with increased risk of disease. For familial hypercholesterolemia, 28 of 131 carriers (21.4%) vs 4,663 of 49,607 noncarriers (9.4%) developed atherosclerotic cardiovascular disease. Further, for hereditary breast and ovarian cancer syndrome, 32 of 116 female carriers (27.6%) vs 2,080 of 27,028 female noncarriers (7.7%) developed associated cancers. For Lynch syndrome, 17 of 76 carriers (22.4%) vs 929 of 49,662 noncarriers (1.9%) developed colorectal or uterine cancer.

The predicted probability of disease at age 75, in spite of contemporary clinical care, was 45.3% for carriers of familial hypercholesterolemia, 41.1% for hereditary breast and ovarian cancer syndrome, and 38.3% for Lynch syndrome. Across the 3 conditions, 39.7% (175 of 441) of the carriers reported a family history of disease vs 23.2% (34,517 of 148,772) of noncarriers. 

“These results build on previous efforts to understand the prevalence and clinical importance of monogenic risk variants in several key ways,” the authors wrote. “Although explicit demonstration that population genomic screening improves outcomes in a randomized clinical trial may not be feasible, identification of pathogenic variant carriers before disease onset may provide a clinically actionable opportunity for targeted screening, early therapy, and cascade testing of first-degree relatives.” 

However, there are key challenges to widespread implementation of population-based genomic screening into clinical practice as described by the researchers. First, the rigorous classification of the individual variants using clinical guidelines would be necessary. This would require the manual curation of evidence, which predominantly relies on “a given variant co-segregating with disease within a family-based study, absence of presence at an appreciable frequency in diverse population databases of genomic variation, and rare allele frequency in global populations.”

Additionally, few health systems have the required personnel and infrastructure to implement genomic medicine. Most electronic health records do not currently allow for structured integration of genetic testing results into patient records, which could lead to inefficiencies and duplicative testing. Further, carriers of monogenic risk variants may infer that they are predestined to develop disease. 

“Additional efforts are needed to integrate genetic and nongenetic factors into integrated risk estimation tools that better facilitate shared decision-making for patients and their health care teams,” the authors wrote. “Moreover, these observations suggest a potential need to alter the current framework for clinical risk disclosure in which risk is described in a probabilistic manner rather than as pathogenic vs not pathogenic.” 



Patel AP, Wang M, Fahed AC, et al. Association of Rare Pathogenic DNA Variants for Familial Hypercholesterolemia, Hereditary Breast and Ovarian Cancer Syndrome, and Lynch Syndrome With Disease Risk in Adults According to Family History. JAMA Network Open