For the First Time, Recommendations Offer Guidance about Incidental Findings in Clinical Genomic Sequencing

For the First Time, Recommendations Offer Guidance about Incidental Findings in Clinical Genomic Sequencing:

Brigham and Women's Hospital, March 21, 2013:


In a highly anticipated report, landmark recommendations on the handling of incidental findings in clinical genome and exome sequencing are being issued from the American College of Medical Genetics and Genomics (ACMG).  A report of the recommendations, led by Robert C. Green, MD, MPH, a medical geneticist at Brigham and Women's Hospital (BWH), outlines for the first time a minimum list of genetic conditions, genes and variants that laboratories performing clinical sequencing should seek and report to the physicians that ordered the testing -- regardless of the original reasons for which the test was ordered. 


"If, as expected, these recommendations are adopted by laboratories and clinicians, they will have important implications," said Green, who also co-chaired the ACMG Working Group that developed the recommendations.  "As clinical sequencing becomes more widespread, laboratories are looking for guidance on how and what should be communicated to clinicians when results are analyzed.  These recommendations will allow a small percentage of families to learn unexpected but potentially life-saving information about an illness they may have never suspected they were at risk for."


The recommendations are the result of a year-long process which included review by outside experts and approval by the ACMG Board of Directors.  Leslie Biesecker, MD, chief and senior investigator of the Genetic Diseases Research Branch at the National Human Genome Research Institute co-chaired the working group with Dr. Green.


"Incidental findings" are health-related interpretations of a patient's genetic code that are unrelated to the primary reason for ordering the genetic testing.  For example, if a clinician orders exome or genome sequencing to analyze genes related to a patient's cardiac condition, the laboratory will already have information about all the other genes in hand and could examine genes for something like cancer predisposition with relative ease.  Should a known or suspected mutation be found in a cancer predisposition gene, the laboratory would report this incidental findings back to the ordering clinician, and the clinician and patient could take steps to screen for cancer.  However, in the absence of accepted guidelines about which variants to search for and which results to return to the clinician, laboratories have been uncertain whether to search for or report results beyond those that the doctor ordered.


"We are at an early stage in the implementation of genomic medicine, and this is a difficult topic to manage because there is not yet much scientific evidence to support whether returning incidental findings can provide medical benefit," said Dr. Green. "Based upon existing evidence and clinical judgment, our Working Group of medical geneticists, genetic counselors, ethicists and molecular laboratorians reached consensus that a small number of conditions, genes and variants were likely to have a positive impact on the health of patients and their families if incidentally identified and reported."


In assembling this list, the Working Group prioritized the disclosure of disorders where:

  • Preventative measures and treatments exist
  • Patients might not experience symptoms for a long period of time
  • The genetic mutations are well recognized and known to have a strong link of causation

Examples of diseases recommended for disclosure include rare hereditary cancers and rare heart diseases that could result in sudden cardiac death.  The full recommendations are available on the ACMG's website.


Because clinical sequencing is an entirely new technology, the recommendations include several provisions that deviate from established practices in medical genetics.   For example, the Working Group did not recommend giving patients a choice of whether or not their physician would receive positive results from the list of recommended incidental findings.  The Working Group also recommended that adult-onset conditions on the list be reported even when the patient is a minor.  Dr. Green acknowledged that these recommendations diverge from current practices in medical genetics, explaining, "Sequencing offers a brand new way of looking at genetic testing.  The Working Group believes that when we can detect findings that could provide clues to a dangerous condition for which a medical intervention may be possible, laboratories and clinicians have a responsibility to alert the patient's physician, as is done in the rest of medical practice."


The report makes it clear that the recommendations are a starting point that will and should be updated regularly as scientific evidence accrues about genetic conditions.  The ACMG will establish an ongoing process for updating the recommendations.

PRE-RA Family Study

National Institute of Health, 2011S000892 (E. Karlson, PI)

Principal Investigator: Elizabeth Karlson


Many family members of people with rheumatoid arthritis (RA) wonder if they are at risk for developing RA. The PRE-RA Family Study is creating an online tool (called the "Personalized Risk Estimator for Rheumatoid Arthritis", or "PRE-RA") to help family members understand and reduce their risk of RA. Our research team, led by Elizabeth Karlson, MD, will enroll 100 people who are at risk of developing RA. This increased risk is related to having a blood relative with RA. Gathering information about who is at risk for RA will be helpful in identifying effective ways to check for or prevent this disease.

The study is enrolling adults between the ages of 18-70 who are first-degree family members of a person with RA. As part of the study, participants are asked to answer some questions about their lifestyle and health behaviors. For some participants, a blood sample will be drawn from their arm, which will be tested for protein and genetic markers. This information will help the team to create an accurate, easy-to-use computer tool to help people at risk of developing RA understand their risk.

Dr. Green's Role: (Consultant) Advising on study design and implementation, with a focus on genetic risk communication.


To learn more about Dr. Karlson's work, please visit Brigham and Women's Hospital