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Exome Sequencing of Volunteers Sheds Insight into How NGS Could be Rolled Out for Adult Screening


An exome sequencing study of 81 volunteers has shed light into how the technology could be rolled out as an adult disease risk screening test.

Researchers from Baylor College of Medicine and the University of Texas Health Science Center performed exome sequencing on 81 business executives to see whether the technology would be useful in identifying pathogenic variants for adult-onset diseases, or alert volunteers of familial genetic disease or carrier status.

The study, which was published online in the Proceedings of the National Academy of Sciences last month, concluded that "replacing traditional methods for genetic testing of inheritable disorders with next-generation sequencing will reduce the cost of genetic testing and increase the information available for the patients."

Thomas Caskey, a professor of molecular and human genetics at Baylor who led the study, told Clinical Sequencing News that he thinks "it is time that we have an adult screening program that identifies the risk of disease before the pathology. … I am absolutely certain that the sequencing of disease genes will identify risk and give us the opportunity to reduce disease and healthcare costs."

The sequencing study originated in 2010 when the Houston chapter of the Young Presidents' Organization, a network of CEOs and other corporate executives under the age of 45, approached Caskey about hosting an educational program on genomics. After the day-long educational program on genome science, of which around 160 individuals of the 450-member YPO group attended, those at the meeting were given the option to participate in a whole-genome sequencing study on the genetics of schizophrenia as members of the control group.

As part of that, Caskey and the group also wanted to study the impact of sequencing to screen for adult disease risk. The volunteers were offered the option of receiving sequencing results, as well as the ability to opt-out of receiving results.

Caskey said that of the 160 individuals that attended the day-long workshop, 81 volunteered to be sequenced and none opted to not receive results. Caskey originally presented on the so-called 'CEO sequencing project' at the combined International Congress on Human Genomics/American Society of Human Genetics conference in 2011 (CSN 11/16/2011).

Caskey also collaborated with Amy McGuire, who directs the Center for Medical Ethics and Health Policy at Baylor, to do extensive follow-up with the volunteers, including asking about their motivations for participating.

"Around 90 percent wanted to find out about personal health and the genetic health of family, including offspring and prior generations," said Caskey.

He said this indicated to him that the group that chose to receive sequencing was skewed, and perhaps not indicative of the general population.

"The people coming in for our study knew they had a health problem or knew that in their family they had a health problem that was possibly genetic," Caskey said. Indeed, Caskey's group was able to link personal disease history with causative variants in 18 volunteers, and by incorporating family history was able to identify an additional five heritable diseases. Since the publication, Caskey said the group has made several more diagnoses for a total of 27 disease diagnoses.

Diagnosed diseases included hypercholesterolaemia, obesity, diabetes, breast or ovarian cancer, prostate cancer, melanoma, follicular thyroid cancer, nonsyndromic deafness, age-related macular degeneration, male infertility, and brittle cornea syndrome.

Familial diseases, in which the volunteer was not affected but potentially had family members affected or that were also carriers, included Prader-Willi syndrome, a rare disorder that often affects muscle tone and causes facial abnormalities and learning disabilities; paraganglioma; Ankylosing spondylitis, an inflammatory disease of the vertebrae; Tourette's; and Parkinson disease.

Caskey said that identifying these familial diseases was especially rewarding. "As we looked at the pedigrees, we could identify heritable disease in the family, but we knew that the volunteer was not the one at risk."

Caskey said that he was then able to discuss with those seven volunteers the potential of "solving the genetic disease" in the family. "That was particularly productive," he said. For instance, he said, upon following up with one family the researchers were able to identify Prader-Willi syndrome in an affected individual who had previously not been diagnosed. The result of that study, which used Complete Genomics' technology, was published recently in Nature Genetics.

Caskey said that sequencing for disease risk could have the greatest impact in the areas of cancer, cardiovascular diseases, and neurodegenerative disease, despite the fact that there is much unknown and the impact of genetics can be complex and require extensive counseling.

Counseling for cancer risk was more time-consuming than counseling for other diseases, the study authors reported. "The concepts of the two-hit hypothesis and 'somatic mutation' were difficult to grasp for the volunteers, even when we discussed the subject in great detail during the education session," the authors wrote. "All volunteers were provided information regarding standard of practice approaches for early detection of the respective cancer."

Regarding cancer risk, 12 volunteers had breast cancer risk alleles. Two with BRCA2 mutations were diagnosed with breast cancer. Eight of the 12 had a family history of the disease, while four had no family history.

Colon cancer risk variants were identified in 10 volunteers, none of whom had the disease. Of those 10, five had a family history.

The team also identified a number of variants for cardiovascular disease risk. Twelve volunteers were affected with various cardiomyopathies for which the pathogenic variant or variants were identified. Additionally, 11 volunteers "had no apparent disease but had a positive family history of tachycardia, sudden death, and [coronary artery disease] and carried risk alleles," the authors wrote.

Caskey said that these individuals in particular represent an opportunity for intervention and monitoring. "That's where the high value is," he said.

Since the study, around 72 percent of the volunteers took their genomic information to their primary care physicians and 25 percent have since reported making modifications because of the results.

Nevertheless, Caskey said that there were still a number of errors, particularly with regards to how mutations are classified in databases. For instance, he said he identified mutations in six or seven individuals that were predictive of diseases they did not have, including a mutation that was predictive of severe mental retardation in one CEO. "This is going to be a problem in the future," Caskey said, as next-generation sequencing tests become more common.

Another issue will be how primary care physicians handle genomic information brought to them by their patients. Caskey said that for the study he spoke with the volunteers' physicians about their genomic reports. He is also doing a similar exome sequencing study of physicians themselves, enabling physicians in the Houston area to receive exome sequencing and personalized disease risk reports.

Going forward, Caskey said that while there are still a number of hurdles to adoption, he thinks that next-gen sequencing has a place in screening for adult disease risk. For instance, he said that personally, he has a strong family history of diseases such as colon cancer, diabetes, and coronary artery disease on his father's side of the family, but no disease risk on his mother's side. "So my personal disease risk is hard to predict without doing genome analysis," he said.

Caskey said that he foresees sequencing being adopted clinically in a number of different scenarios. While whole-genome sequencing will ultimately provide the most utility, he said, because the medical field is so specialized, targeted sequencing will likely be done initially. A cardiologist would only want to know about cardiovascular disease risk, for instance, and would have no idea how to interpret variants related to cancer, Caskey said.

Another scenario he envisions is whole-genome sequencing being done either by academic institutions or private companies, with physicians ordering specific reports related to their specialty.

Such tests will also need to be covered by insurance companies, which Caskey anticipates will happen with time. "It's already happening in cancer and cardiomyopathy," he said.

Similar to other experts that are looking to move next-gen sequencing into clinical care, Caskey said that errors in the databases will need to be corrected. "Sequencing is not the problem anymore," he said. "The databases need to be strengthened and the reports need to be made very clear in what the risk is and what can be done about it."