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The Whole Genome Laboratory at Baylor College of Medicine. From left: Dr. Yaping Yang, Dr. Richard Gibbs, Dr. Christine Eng and Donna M. Muzny, M.Sc.

For some patients with suspected genetic diseases, the search for answers becomes a medical odyssey that can consume precious time and resources.

In a report in the New England Journal of Medicine, researchers at Baylor College of Medicine describe how a new genetic test called whole exome sequencing which determines the DNA sequence of the exons or protein-coding regions of thousands of genes simultaneously, using next-generation sequencing techniques, provided a diagnosis to 25 percent of the first 250 such patients referred to the Baylor Whole Genome Laboratory, demonstrating the value of such technology to individual patients.

"This is an important new diagnostic tool to help us find answers for our most challenging patients and their families, many of whom have been searching for a diagnosis for years," said Dr. Christine Eng, professor of molecular and human genetics at BCM, senior director of the Medical Genetics Laboratories and medical director of the Whole Genome Laboratory at BCM. She is also senior author of the report. "Physicians discussed the test with their patients and family members and sent samples to our clinical diagnostic lab for whole exome sequencing. With this test, we were able to achieve answers for about 25 percent, which is a higher positive rate than standard genetic tests like karyotyping."

New form of genetic testing

"This is a relatively early stage for the introduction of this technology to medical care," she said. "Many of the answers dealt with genes that only recently became associated with diseases. New discoveries of disease genes are being made every day and these findings will help us improve our diagnosis rate even more. In addition, we are learning more about the phenotypic spectrum (the signs and symptoms) of both rare and well-known genetic disorders."

"It has been very rewarding to work as a large team to develop this new form of genetic testing that provides a better understanding of disease in these very complex patients," said Dr. Sharon Plon, professor of pediatrics - oncology and molecular and human genetics at BCM and an author of the report.

"This is a good example of translating the knowledge and technology developed through the Human Genome Project into clinical medicine available to physicians worldwide," said Dr. Richard Gibbs, director of the BCM Human Genome Sequencing Center and another author of the report. "This program may enhance the way we make future discoveries in genetic medicine. Depending on an individual’s results, he or she may have the opportunity to participate in research studies that are expanding knowledge and will eventually be useful back in the clinic."

Eighty percent of the 250 patients in the report were children with symptoms that indicated neurologic disorders. In 62 of the 250, Eng and her colleagues identified 86 mutated genes that they believe were associated with the disorders seen in the patients. In 33 patients, the mutated gene was autosomal dominant, meaning that only one copy of the mutated gene was necessary to cause the disorder. Another 16 had a recessive gene mutation. In this case, the child must inherit two mutated genes - one from the mother and one from the father - to have the disease. Nine of the patients had mutated genes on their X chromosomes - so called X-linked diseases that more often affect boys, who have only one X chromosome. In 83 percent of the patients with dominant mutations and 40 percent of those with an X-linked disease, the mutation was not inherited from a parent. In the language of genetics, these occurred de novo or for the first time in these families.

Four of the patients were found to have two diagnoses, each caused by a mutation in different genes. This was unexpected since physicians usually try to find one diagnosis that explains most of their patient’s signs and symptoms. In these patients, two conditions may have "blended" and made it difficult for the doctor to recognize the multiple diagnoses.

Next-generation sequencing

"To accomplish this, the laboratory performed whole exome sequencing on the patients who had a high likelihood of having a genetic disorder, using next-generation sequencing, a high-throughput, high-tech procedure which produces millions of DNA sequences," said Dr. Yaping Yang, associate professor of molecular and human genetics at BCM and the first author of the report. "The huge quantity of sequence data is then carefully analyzed to identify mutations and determine if they are causative of the patient’s medical issues. If a physician thinks a patient’s disease has a genetic basis, whole exome sequencing is a strategy to consider. Before, physicians did not have this option."

Eng said that being able to give patients a diagnosis is positive. For some cases, there may be the direct benefit of an available treatment. While for most there will be no treatment or cure, often knowing the cause of the disease enables physicians and parents to manage the patients’ symptoms better, to obtain necessary services, and to better prepare for the future, including knowing the risk of having a second child with the same problem.

Many insurers covered the estimated $7,000 cost of the test, said Eng. It may take persistence and communication between the doctor and insurance carrier in order to explain the benefit of the new test and how it might actually save health care dollars if a diagnosis is arrived at sooner.

The costs of such tests will go down as technology improves, she said.

In the future, she said, she hopes that experts will be able to determine the best time to suggest exome sequencing.

"For the most part, testing in this group of 250 patients was ordered fairly late in the diagnostic process after many different genetic tests failed to arrive at an answer," said Eng. "We have to figure out the most efficient way to use this test. Should it be more in the beginning of the workup or after other avenues have been exhausted?"

Increase in physician orders

Eng says that the lab is seeing an increase in physician orders for whole exome sequencing. As of mid-September, results from more than 1,700 such cases had been completed in the laboratory.

Eng says that is it important to understand that whole exome sequencing can lead to unexpected results. Since an individual’s whole exome is being looked at they may learn more about their medical status than they were expecting, she said. They may find that they are at increased risk of developing cancer or heart disease in the future. That is why discussing the testing and results with a doctor or a genetic counselor is essential.

The BCM Whole Genome Laboratory is a joint effort of BCM’s Human Genome Sequencing Center and the Medical Genetics Laboratories of the Department of Molecular and Human Genetics.

Others who took part in this work include Donna M. Muzny, M.Sc.; Jeffrey G. Reid, Ph.D.; Matthew N. Bainbridge, Ph.D.; Alecia Willis, Ph.D.; Patricia A. Ward, M.S.; Alicia Braxton, M.S.; Joke Beuten, Ph.D.; Fan Xia, Ph.D.; Zhiyv Niu, Ph.D.; Matthew Hardison, Ph.D.; Richard Person, Ph.D.; Mir Reza Bekheirnia, M.D.; Magalie S. Leduc, Ph.D.; Amelia Kirby, M.D.; Peter Pham, M.Sc.; Jennifer Scull, Ph.D.; Min Wang, Ph.D.; Yan Ding, M.D.; Sharon E. Plon, M.D., Ph.D.; James R. Lupski, M.D., Ph.D.; Arthur L. Beaudet, M.D.; and Richard A. Gibbs, Ph.D., all of BCM.

Funding for this work came from National Human Genome Research Institute (Grants U01 HG006485-01 to Plon and U54-HG003273 to Gibbs).

Find more information on whole exome sequencing.

View videos of the conferences at which such results are announced.