NEW YORK – Investigators involved in the third phase of the Electronic Medical Records and Genomics Network (EMERGE III) have tracked the frequency and type of secondary or incidental findings that occur in diverse participants who were profiled with targeted panel sequencing, uncovering reportable findings in some 3 percent of those individuals.
"These important findings serve as a resource to inform decision making in patients and research participants undergoing genomic testing, aid the ongoing development of practice standards and guidelines in genomic medicine, and drive future research efforts in variant interpretation and [secondary finding] return," first and corresponding author Adam Gordon, a researcher affiliated with Northwestern University and the University of Washington, and his co-authors wrote.
As they reported in a study published in Genetics in Medicine on Wednesday, the researchers searched for medically actionable incidental findings, and their frequencies, in 21,915 EMERGE III network participants who were assessed with a 109-gene "EMERGEseq" panel at CLIA-certified sequencing labs. For their analysis, they focused on risk variants in 67 genes and another 14 SNP sites.
"A primary goal of EMERGE III is to harmonize and implement an entire, unified pipeline simulating real-life clinical genomic testing within a broad spectrum of participants and clinical settings, with each site's cohort of [around] 2,500 participants being, by design, markedly different in ascertainment strategy and demographics," the authors explained.
The team found that more than 2.5 percent of participants, who were enrolled at 10 sites in the US, carried pathogenic or likely pathogenic variants in one or more of the 59 genes flagged for reporting by the American College of Medical Genetics and Genomics (ACMG), while a further 0.48 percent carried clinically actionable changes in the other genes and SNPs considered.
All told, the investigators discovered 661 actionable incidental findings, including 556 pathogenic or likely pathogenic variants in ACMG 59 genes and 105 incidental findings involving actionable variants in relatively high-penetrance risk genes such as PALB2 or MEFV. They noted that 10 individuals had secondary findings involving two different risk variants.
In general, the incidental findings turned up most frequently in genes related to cancer susceptibility, which appeared prone to pathogenic variants, followed by cardiovascular disease risk genes containing likely pathogenic variants.
By characterizing such variants in a relatively diverse group, the authors hoped to provide a clearer picture of the incidental findings that turn up across the "ACMG 59" genes and beyond in individuals profiled by panel testing or other genomic analyses.
"One major challenge to the application of the ACMG secondary findings guidelines is that, to date, much of the expert opinion regarding actionability of these gene-disease pairs does not derive from the experience of testing the broader patient populations that these guideline are primarily intended to support," the authors explained.
When they took the participants' self-reported ancestry into account, the researchers saw secondary findings in a similar proportion of individuals from different ancestry groups — but only after excluding a risk allele in the hemochromatosis-related gene HFE that is known to occur with enhanced frequency in individuals with European ancestry.
They cautioned that the current analysis did not include Ashkenazi Jewish individuals, who typically have a one in 40 chance of carrying risk-enhancing founder alterations in the breast and ovarian cancer-related genes BRCA1 and BRCA2.
Even so, the authors noted that "removing known [Ashkenazi Jewish] founder alleles from the analysis does not alter our findings that [secondary findings] are most likely to be in genes associated with cancer risk, though a previous study found the highest rate to be in genes associated with cardiac disease."