Genome Advance of the Month
Pilot study eyes implications of ACMG stance on incidental findings
By Anh Quynh Nguyen
NHGRI Scientific Program Analyst
In March 2013, the American College of Medical Genetics and Genomics (ACMG) released a recommended list of 56 genes that laboratories and clinicians must report back to patients should incidental findings be found. The genes on the ACMG's list are all genes where mutations can cause serious, but treatable, health conditions (known as actionable findings). In April 2013, the ACMG clarified that it would be deemed "unethical" if these findings were not reported.
November's Genome Advance of the Month highlights a pilot study that attempts to estimate the number of expected actionable findings per individual. The authors also critically discuss the potential burden incidental findings can place on the healthcare system, and the ever-growing need for an adequate clearinghouse that healthcare providers can use to identify harmful mutations with sufficient rigor for use in clinical care. Finally, the study raises a concern about health disparities resulting from genetic testing.
The paper, published in October by The American Society of Human Genetics, first expands the ACMG's list of actionable genes from 56 to 114. These genes were identified by the Clinical Sequencing and Exploratory Research (CSER) "NEXT" Medicine Return of Results Committee (RORC), funded by the University of Washington and the National Human Genome Research Institute.
Of the 6,503 participants of the National Heart, Lung, and Blood Institute Exome Sequencing Project, 500 participants of European descent and 500 participants of African descent were selected for the screen. Within the participants' 114 genes of interest, 239 unique variants were identified, which were considered to be disease-causing by the Human Gene Mutation Database (HGMD). However, there has been no further definition of, or guidelines on how to find out how many of these "disease-causing" variants are pathogenic mutations, which brings us to what the researchers set out to answer with this study.
The study came up with stringent criteria to categorize the variants into four categories: pathogenic variants; likely pathogenic variants of uncertain significance (VUS); VUS; and likely benign VUS. The study also included additional mutations that were not listed in HGMD, and took into account the minor allele frequency (MAF). The higher the MAF, the more common the variant, and if the MAF is above a certain threshold level, the variants will be too common to be highly penetrant pathogenic variants. Once the frequency of these variants was taken into account, 72 of the 239 variants were no longer considered pathogenic.
All of the variants from HGMD, and a few outside of HGMD, were reviewed by 19 expert reviewers-some were double-reviewed for quality control-and the entire list of variants was overseen by a genetic counsellor. Through various review processes, the study found that only 23 (out of 1,000) participants had pathogenic or likely pathogenic mutations of one or more of the 114 actionable genes. More specifically, only 7.5 percent of the variants classified by HGMD as disease-causing were found to be pathogenic or likely pathogenic. While it is good news that the number of these variants is a lot lower than the number of "disease-causing variants", it also underscores the fact that we still lack a database that properly identifies pathogenic mutations for use in clinical care. Moreover, the study also suggests that HGMD is oversensitive and not specific, as it does not take MAF into account or categorize different levels of pathogenicity in the variants.
One of the reasons that incidental findings are such a hot topic among researchers right now is down to whether or not an investigator has a duty or responsibility to actively look for actionable incidental findings (and then inform the participant) in the course of conducting genomic research. An important finding from this study involves the length of time required to review the evidence for the genes of interest; the whole review process took about 92 hours with an average of 23 minutes of expert review time per unique variant, a not-insignificant amount of time.
Last but not least, the study highlights further increases in health disparities as a result of genetic testing. Only 94 out of 239 unique variants were found in those of African descent. Out of the 18 participants that had likely pathogenic or pathogenic mutations, only three were of African descent. According to the authors, this could be explained by insufficient genetic literature on variants in the African population, a concern for which the research community is becoming ever-more conscious. Therefore, genetic testing is currently more helpful for those of European descent, and this disparity will exacerbate unless more ethnically diverse populations are included in genetics and genomics studies.
The study does not directly recommend any method for identifying pathogenic mutations to tackle the problem of the return of incidental findings. However, the results provide insights for researchers to find a solution to this issue and will hopefully help with policy-making decisions in the future.
Read the article
Dorschner MO, Amendola LM, Turner EH, Robertson PD, Shirts BH, Gallego CJ, Bennett RL, Jones KL, Tokita MJ, Bennett JT, Kim JH, Rosenthal EA, Kim DS; National Heart, Lung, and Blood Institute Grand Opportunity Exome Sequencing Project, Tabor HK, Bamshad MJ, Motulsky AG, Scott CR, Pritchard CC, Walsh T, Burke W, Raskind WH, Byers P, Hisama FM, Nickerson DA, Jarvik GP. Actionable, Pathogenic Incidental Findings in 1,000 Participants' Exomes. The American Journal of Human Genetics. 93(4):631-=40. 2013. [PubMed]