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Healthy volunteers benefit from whole exome sequencing

When Dr. C. Thomas Caskey, professor of molecular and human genetics at Baylor College of Medicine  and his colleagues signed up members of the Houston Chapter of the Young Presidents’ Organization (YPO) as "controls" in a whole exome sequencing project, he and his colleagues knew that there was a likelihood that some of the volunteers would discover information about their own health.

In a report that appears online in the Proceedings of the National Academy of Sciences, Caskey, first author Dr. Manuel L. Gonzalez-Garay, assistant professor in the Center for Molecular Imaging at The University of Texas Health Science Center at Houston and Dr. Amy McGuire, director, and Stacey Pereira, both of the Baylor Center for Medical Ethics and Health Policy, describe not only what they found, but how the volunteers accepted and dealt with the information. (The YPO is an international organization made up of people ages 45 years and younger who are chief operators [president, managing director, chairman, etc.] of companies that meet size and revenue requirements.)

"We found that people accepted this information and acted on it," said Caskey. "We were ahead of the field in showing you could sequence a person’s exome and tie it back to their medical history and pedigree (the genetic history of their parents and ancestors) to make health care recommendations and therapeutic decisions."

In the study, Gonzalez-Garay oversaw next generation exome sequencing on 81 volunteers. (The exome is the part of the genome that carries the genetic blueprint for proteins. Next generation refers to the high-tech, high-throughput techniques used to determine the individual blueprint of a person and analyze what it means.) The researchers also obtained the volunteers’ personal medical histories and did a three-generation pedigree. To insure that they understood the implications of the research and the findings, Caskey and the others asked the volunteers to take part in a comprehensive educational program about genomics and genetics and its individual implications.

This training was planned by the Young Presidents’ Organization education committee led by Dr. Arthur Sands, president and chief executive officer of Lexicon Pharmaceuticals, and Stuart Gaylor, president of Al’s Formal Wear. (Sands received his Ph.D. and M.D. from Baylor College of Medicine.) The initiative won the Houston chapter the "Best Innovative Event" from YPO International for 2010-2011.

Among these volunteers, they found 273 gene copies (alleles) that were recessive. (People are born with a recessive genetic disease when they inherit two recessive or mutated copies of a gene - one from the mother and one from the father.) They found 152 dominant risk alleles in 101 genes. (A dominant genetic disease is one in which inheriting a single mutated copy of a gene can result in disease.) They also found 10 recessive risk alleles on the X-chromosome. Such X-linked diseases occur most often in boys, who have only one copy of the disease gene, which is not located on the Y chromosome. If it is mutated, they develop or are born with the disorder.

In 24 volunteers, when they linked personal disease histories to the exome findings, they identified the gene at fault. When they incorporated family history into the picture, they found an additional six heritable diseases.

All volunteer received genetic counseling. In a follow-up study, McGuire and Pereira found that 72 of the volunteers told their personal physicians about the finding and 25 percent said they had changed their behaviors because of the results. Even though the volunteers could have had the individual findings involving single genes validated in another laboratory with an approved test for that gene, 78 percent said they had not done this.

"Many of these volunteers did so because they either knew they had a disease or they had a family member with the disease," said Caskey. "That gave our finding a self-selection bias." They followed up each case with a referral to a qualified genetics program with diagnostic capacity for confirmation of the suspected genetic disease.

While the scientists analyzed the information for risks of cancer, heart disease, neurodegenerative and obesity/diabetes, they noted that considerable education was required to differentiate risk from diagnosis.

"Sequencing serves as a new screening risk detection approach toward the objective of improved health," the authors wrote. "It is expected that genomic studies will increase surveillance studies (colonoscopy, gynecologic examinations, mammograms, cardiovascular analyte/scanning studies) but has the possibility of more precisely identifying the patients who may benefit from disease prevention surveillance."

The authors also noted that there are limitations to the technique and they limited themselves to reporting those results of which they were most confident and for which there was the most scientific validation.

With more information such analyzes will become even more valuable. They can be stored and physicians/genetics experts can refer to them as new information, new disease genes and new science becomes available, said Caskey.

Caskey plans to expand this program with other YPO organizations, starting in Austin.

Funding for this study came from the Cullen Foundation for Higher Education to Caskey and Dr. Richard Gibbs, director of the Baylor College of Medicine Human Genome Sequencing Center, and the Governing Board of the Greater Houston Community Foundation.

McGuire holds the Leon Jaworski Professorship in Biomedical Ethics.

For more information on research at Baylor College of Medicine, please go to From the Labs.