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Whole-Genome Sequencing, Deep Phenotyping Shows Many Adults Harbor Pathogenic Genetic Variants

NEW YORK – About 1 in 6 adults harbor at least one pathogenic or likely pathogenic genetic variant, researchers from precision health firm Human Longevity have found in a new study. They further reported that nearly 12 percent of those adults have phenotypic evidence that supports the clinical diagnosis of a genetic disorder.

Almost 1,200 adults underwent evaluation using Human Longevity's Health Nucleus platform, which combines whole-genome sequencing with deep phenotyping, including advanced imaging, metabolomics, and other clinical laboratory tests. As the researchers reported recently in the Proceedings of the National Academy of Sciences, they found actionable results throughout their cohort. This approach to assessing health, they said, could help detect disease early on and tailor treatments. 

"The goal of precision medicine is to provide a path to assist physicians in achieving disease prevention and implementing accurate treatment strategies," senior author Thomas Caskey, chief medical officer of Human Longevity, said in a statement. "Our study showed that by employing a holistic and data-driven health assessment for each individual, we are able to achieve early disease detection in adults." 

For this study, the researchers sequenced and deeply phenotyped 1,190 self-referred volunteers. The cohort was largely male with a median age of 54 years. While members of the cohort did have preexisting conditions such as heart disease and diabetes, it was not enriched for common adult chronic diseases, as compared to the National Health and Nutrition Examination Survey.

Phenotypic testing found that more than a third of participants had insulin resistance or impaired glucose tolerance, about 30 percent had elevated liver fat, and about 11 percent had risk of coronary heart disease. These, the researchers noted, are highly actionable findings, many of which were not known prior to participants' assessments.

Following filtering and interpretation, they found 17.3 percent of participants had at least one medically significant genetic finding, a variant classified as pathogenic or likely pathogenic. The most common affected genes in this cohort for autosomal dominant conditions include CHEK2, MYBPC3, and BRCA2, while the most common affected genes for recessive conditions were HFE, BTD, and GJB2.

By folding in participants' clinical and phenotypic characteristics, the researchers were able to make genotype and phenotype associations for 11.5 percent of participants. For instance, one individual with a likely pathogenic variant in the HNF1B gene had imaging results reflecting multiple bilateral kidney cysts smaller than a centimeter in size and metabolomic findings indicating impaired glucose tolerance.

The researchers cautioned, though, that the identification of a pathogenic genomic variant is not the same as a clinical diagnosis. They noted that 30 of the 69 participants in their cohort with cancer-related pathogenic or likely pathogenic variants did not have a family history of disease or a related phenotype. This could be due to incomplete penetrance, variable expressivity, delayed disease onset, or non-pathogenicity, the researchers noted.

More than 86 percent of participants had at least one autosomal recessive variant associated with disease, and some of these individuals had phenotypic manifestations. For instance, 18 percent of the individuals who were heterozygous for an HFE variant associated with hemochromatosis had a high marker of liver iron content, which could have health consequences.

"This study shows that the definition of 'healthy' may not be what we think it is and depends upon a comprehensive health evaluation," author Craig Venter, founder of Human Longevity, said in a statement. "The data underscore Human Longevity's innovative approach to helping clinicians with early detection and personalized treatments, potentially achieving better health outcomes for patients."