Study Finds Individuals Carry Genetic Variants for Actionable Monogenic Disorders


Approximately 1 in 6 healthy individuals who underwent proactive genetic screening had genetic variants linked to increased risk for developing medically actionable disorders, including certain cancers and cardiovascular disorders.

Nearly 1 in 6 individuals screened for genetic variants associated with actionable monogenic disorders was found to have clinically significant results, representing early evidence that proactive genetic screening can be helpful in determining personal health risks and improving public health outcomes, according to a recent study.

The large multicenter cohort study, published in BMC Medicine, is one of the first analyses to examine real-world examples of specialists and primary care providers using genetic screening with a targeted multigene panel to classify health risks in patients.

“These data also provide a foundation for further studies to assess the role of genetic screening, as part of regular medical care, in reducing morbidity and mortality from actionable genetic disorders and to determine its clinical utility and cost-effectiveness,” wrote the investigators.

Screening for genetic risk for monogenic disorders in healthy people has mostly been limited to prenatal carrier and newborn screening for severe autosomal recessive or X-linked disorders. However, emerging evidence supports primary genetic screening for some hereditary disorders, such as hereditary breast and ovarian cancer.

The American College of Medical Genetics and Genomics (ACMG) has made recommendations for the analysis of clinically significant variants within 59 genes associated with adult-onset cancers and cardiovascular disorders as optional secondary findings from exome or genome sequencing. The investigators reviewed the genes on ACMG list and gene lists used by clinical centers that work on research related to reporting personal risk for monogenic disorders.

For the study, health care providers from a variety of domestic and international clinical settings, including primary care, executive health, hereditary cancer, and cardiovascular risk clinics, offered patients 18 years or older a proactive genetic screening test. Personal and familial health histories were examined when available, and all samples were returned between January 2016 and May 2020.

Among the 10,478 adults who underwent proactive screening and genetic analysis, the average age was 49.5 years, 59.0% (n = 6177) were women, and 59.9% (n = 6274) were Caucasian. The results showed that 1619 (15.5%) people had a personal risk for an actionable monogenic disorder, of whom 138, representing 1.3% of the total cohort and 8.5% of all positive findings, had multiple variants related to risk for multiple clinical conditions.

Overall, there were 4637 clinically significant sequence variants representing 611 individual variants. Additionally, 6.2% (n = 649) of all patients were positive for a genotype with high impact and 9.3% (n = 970) were positive for a genotype with moderate impact.

Of all the positive results, 49.8% (n = 807) had disease-predisposing variants that are associated with hereditary cancer syndrome, with variants in genes linked to colorectal cancer accounting for the highest percentage of reported alleles, followed by variants related to breast cancer, breast and ovarian cancer, and melanoma.

Variants in genes associated with cardiovascular disorders were found in 608 (37.6%) of the 1619 people who had positive results. Of the positive cardiovascular disease findings, 158 were high-impact variants, of which 88 were related to arrhythmias, aortopathies, or cardiomyopathies; 45 were linked to familial hypercholesterolemia; and 25 were related to rare forms of hereditary thrombophilia.

When the results were restricted to only 59 genes recommended by the ACMG, the positive yield among the cohort was 5.2% when including all high-impact pathogenic or likely pathogenic variants and all moderate-impact variants.

“Because of the persistent shortage of genetics professionals, consideration and research must continue to be devoted to developing these models as well as scalable mechanisms for communicating genomic test results to more individuals and coordinating appropriate medical follow-up,” the investigators wrote.


Haverfield EV, Esplin ED, Aguilar SJ, et al. Physician-directed genetic screening to evaluate personal risk for medically actionable disorders: a large multi-center cohort study. BMC Med. 2021;19(1):199. doi:10.1186/s12916-021-01999-2

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