BALTIMORE – Participants in a study of the clinical implementation of genome sequencing-based preconception carrier screening overwhelmingly chose to receive all categories of results they were offered and handled uncertain or unexpected results remarkably well, though the time required for genetic counseling was considerable, according to new research presented at the American Society of Human Genetics annual meeting here on Thursday.
The study, called NextGen, is led by researchers at the Kaiser Permanente Northwest Center for Health Research and is part of the National Human Genome Research Institute's Clinical Sequencing Exploratory Research (CSER) program.
At the meeting, Tia Kaufmann, one of the investigators, presented results on choices made by patients regarding the return of results and the psychosocial impact of adverse results they received. Pat Himes, also from the Kaiser Permanente team, provided an analysis of the time for genetic counseling involved.
The study, which runs over four years and is ongoing, has been enrolling non-pregnant women who are seeking or previously received preconception carrier testing, in most cases for cystic fibrosis. Of those, 120 are randomized to undergo genome sequencing and receive results on 750 carrier conditions and about 100 secondary findings, while 200 others receive usual care. Of those receiving positive results from the genome test, 60 are invited to have their male partners be tested by genome sequencing as well.
Focus groups showed that study participants would like to have a choice about the results they receive, but letting them choose from all possible results would be a challenge, Kauffman said. For that reason, the researchers divided the carrier conditions into six categories and let participants select which of these to include in their results. One category, lifespan-limiting conditions, was mandatory, but the other five — serious, mild, and unpredictable outcomes, adult-onset diseases, and medically actionable secondary findings — were the participants' choice.
So far, 192 women have been enrolled in the study, 73 have undergone genome sequencing and 30 had their partners tested as well. In total, 90 percent of women requested to receive results in all categories, and in the "secondary findings" category, all women but one asked to receive their results. Of the 50 couples so far who both received results, two were found to be carriers for the same conditions.
In a number of cases, Kauffman reported, the test results were immediately relevant to patients' healthcare or family planning. In one case, for example, the participant was unknowingly pregnant with a male fetus at the time of testing and turned out to be a carrier for an X-linked disorder, for which she had no family history. She opted to forego prenatal testing but said she felt positive about having the result because it could inform healthcare for her future child if he turned out to have the condition.
In a second case, a woman's partner, who received genome testing because she was a carrier for two conditions, turned out to have a mutation in one of the BRCA genes. Neither his mother nor any of his female relatives, of which there were few, had a history of cancer. Kauffman said he was comfortable receiving the information, stating that he had been aware of the possibility of an adverse result from his genome. She added that his mutation likely "would never have been identified clinically" without the carrier test because he was not a candidate for BRCA screening.
A third participant received a mutation implied in a condition that required additional RNA testing to confirm pathogenicity, but her husband tested negative. The couple was interviewed multiple times along the way and reported not being worried about the results.
Overall, Kauffman noted, the study subject handled uncertainty and unexpected results much better than the researchers had expected. "There was a lot more anxiety in our team and much less anxiety among participants," she said.
Pat Himes, in her talk, focused on the time related to genetic counseling services for the study. Three clinical genetic counselors are involved, she said, both in consenting subjects and in returning results to those receiving genome sequencing.
Genetic counseling services are required at three stages, she said — before, during, and after a participant's visit. Almost 70 percent of participants so far turned out to be carriers for at least one and up to five conditions. While many of those were common conditions, almost 60 percent were rare ones, meaning genetic counselors had to spend considerable time prior to the visit to compile information about the conditions, which is often hard to come by in an easy-to-understand format. In total, genetic counselors spent between 40 and 280 minutes per participant, with most of that time spent on prep time, in particular for very rare conditions.
According to a back-of-the-envelope calculation by a health economist, Himes said, offering genome-based preconception testing to all 500,000 individuals covered by Kaiser Permanente Northwest, which would result in approximately 500 tests per year with an expected 350 positive results, would require half a genetic counselor position, though this is likely an underestimate. One way to address the rising costs for genetic counseling would be to gather standardized information on rare conditions, which could reduce prep time.
Future work will include a cost-effectiveness study to see how medical care changes based on the test results, she said.