Whole-genome sequencing finds rare genetic disease risk in 1 of 5 healthy adults

While some primary care physicians may be able to manage genomic information appropriately, findings could prompt increased health care use with limited clinical value, the researchers said.


Whole-genome sequencing found risk for rare genetic disease in one in five generally healthy patients seen in a primary care setting, a study found.

Most of the genetic findings were not associated with clinical features of disease and prompted little anxiety in patients, but there were modest increased costs for evaluation of the findings, according to the study.

One hundred patients seeing nine primary care physicians at academic medical centers were randomly assigned 1:1 to receive a family history (FH) report alone or in combination with a whole-genome sequencing report (FH + WGS), which included monogenic disease risk results (associated with Mendelian disorders), carrier variants, pharmacogenomic associations, and polygenic risk estimates for cardiometabolic traits. Each patient met with his or her primary care physician to discuss the report. Results were published online June 26 by Annals of Internal Medicine.

The researchers found that 22% (95% CI, 12% to 36%) of generally healthy adult patients with whole-genome sequencing results had a previously unrecognized variant with potential risk for a rare Mendelian disease. However, only about 4% had a clinically relevant abnormality. Only two patients (4%; 95% CI, 0.01% to 15%) had evidence of the predicted phenotypes (fundus albipunctatus due to RDH5 and variegate porphyria due to PPOX).

Primary care physicians were generally able to manage findings appropriately, the study found, recommending new clinical actions for 16% (95% CI, 8% to 30%) of FH patients and 34% (95% CI, 22% to 49%) of FH + WGS patients. Thirty percent (95% CI, 17% to 45%) and 41% (95% CI, 27% to 56%) of FH and FH + WGS patients, respectively, reported making a health behavior change after six months. Geneticists rated primary care management of eight of the Mendelian risk results (73% [95% CI, 39% to 99%]) as appropriate and management of two results (18% [95% CI, 3% to 52%]) as inappropriate.

Health care costs in the six months following disclosure averaged about $300 greater per patient for those in the sequenced group: $1,490 (median, $694; range, $0 to $15,026) versus $1,142 (median, $548; range, $0 to $10,704). Investigators also found that whole-genome sequencing did not seem to cause patient anxiety or depression.

While some primary care physicians may be able to manage genomic information appropriately, findings could prompt increased health care use with limited clinical value, the researchers said. “As the demand for genetics professionals exceeds supply, these preliminary data suggest that PCPs [primary care providers] are readily able to recognize when to refer a patient with WGS for genetics consultation. The recommendations generated by our panelists may help guide nongeneticist physicians faced with managing a genome variant in an asymptomatic patient,” they wrote.

An editorial noted that taking a family history even without a whole genomic sequence produced substantial increases in risk identification and medical care utilization.

“These findings demonstrate that genetic variants indicative of disease risk, carrier status, or altered response to medications are frequent (indeed, universal) and that primary care physicians are largely capable of managing such findings,” the editorial noted. “Healthy patients tolerate this information well, and many report making health behavior changes that could be considered salutary.”