Exome Sequencing Becoming A Powerful New Diagnostic Tool For Genetic Disorders

Chuck Bednar for redOrbit.com – Your Universe Online
Scientists at the Baylor College of Medicine Medical Genetics Laboratories and the UCLA Clinical Genomics Center are at the forefront of a new technique that could be a powerful tool for diagnosing rare genetic conditions.
The technique is known as whole-exome sequencing and involves using cutting edge sequencing techniques to analyze the coding regions or exomes of thousands of genes at the same time, Baylor researchers Dr. Yaping Yang, Dr. Christine M. Eng and their colleagues explained in a recent edition of the Journal of the American Medical Association (JAMA).
Sequencing a patient’s exome and comparing it to a normal reference sequence allows researchers to identify variations in that individual’s DNA sequence. Those variations can then be related back to the patient’s health issues in an attempt to locate the specific genetic cause of that medical condition, the authors added.
The researchers studied a group of 2,000 patients that had been referred for evaluation of suspected genetic conditions, and found that the use of whole-exome sequencing led to the discovery of a molecular diagnosis (meaning that a genetic mutation or variation associated with a specific disease) in roughly 25 percent of them.
“The findings in this report, I believe, will forever change the future practice of pediatrics and medicine as a whole,” study co-author Dr. James R. Lupski, a professor of molecular and human genetics and pediatrics at Baylor, said in a statement. “It is just a matter of time before genomics moves up on the physician’s list of things to do and is ordered before formulating a differential diagnosis. It will be the new ‘family history’ that, better yet, gets you both the important variants inherited from each parent and the new mutations that contribute to disease susceptibility.”
In the study, the use of whole-exome sequencing identified ways in which medical professionals could clinically intervene in order to alleviate or eliminate symptoms and give patients’ families more information about the disease and treatment. Furthermore, many of the diagnoses made using the technique involved patients inheriting a new mutation previously undetected in their parents, the researchers will report Tuesday at the annual meeting of the American Society of Human Genetics (ASHG) in San Diego.
The clinical whole-exome sequencing analyzed as part of the study took place between June 2012 and August 2014, and the tests had been ordered by the patient’s physician for suspected genetic conditions. The process involved the collection of peripheral blood, tissue, or extracted DNA samples which were collected from patients or their parents, and the majority (87.8 percent) of those analyzed were found to have neurological disorders or developmental delay.
A molecular diagnosis was reported for 504 patients (25.2 percent), with 58 percent of the diagnostic mutations not previously reported, the researchers said. Molecular diagnosis rates for the physical manifestation or phenotypic category was 27.2 percent for the neurological group, 24.6 percent for the neurological plus other organ systems group, 36.1 percent for the specific neurological group, and 20.1 percent for the nonneurological group.
“Clinical exome sequencing can assist diagnosis in a wide range of disorders that are diagnostic dilemmas,” said Lupski. “Rare variants and Mendelian disease are important contributors to disease populations… We find ‘rare variants’ in aggregate actually contribute to disease susceptibility in a big way. The individual diseases may be rare, but there are thousands of such diseases and many more being defined through genomics.”
“I expect that in a few years, we will learn of the importance of whole exome sequencing in adult medicine and in fields of pediatrics outside of development,” added Dr. Sharon Plon, professor of pediatrics and molecular and human genetics at Baylor and director of the Baylor Cancer Genetics Clinic. “We are currently performing an NIH-supported clinical trial of whole exome sequencing in childhood cancer patients to learn of its potential utility for these patients.”
Like the Baylor College of Medicine Medical Genetics Laboratories, the UCLA Clinical Genomics Center is working to put DNA sequencing to clinical use, and in research also published in JAMA, they revealed that exome sequencing was able to provide a definitive diagnosis in 40 percent of the university’s most complex cases involving children with rare genetic disorders.
“Our study is the first to show that sequencing a child’s genome together with his or her parents’ dramatically improves geneticists’ ability to reach a firm diagnosis in rare disorders,” said corresponding author Dr. Stan Nelson, a professor of pathology and laboratory medicine at UCLA’s David Geffen School of Medicine. “We discovered a genetic cause for the conditions affecting 40 percent of the hundreds of young children who come to UCLA for exome sequencing due to developmental delays or intellectual disabilities.”
Nelson and his colleagues worked on their research for two-years, sequencing and analyzing the exomes of 814 children whose symptoms had previously defied diagnosis despite exhaustive genetic, biochemical and imaging tests by clinical workers. They took the raw data from the sequencing of those youngsters’ genomes and their parents and set out to identify variants from the standard human genome, then applied a series of filters based on family history and other key factors and looked for genes and mutations that matched the patient’s symptoms.
“Finally UCLA’s Genomics Data Board, a multidisciplinary team of experts, reviewed the findings to reach a diagnosis,” the university said in a statement. “The typical turnaround time is under eight weeks, though test results have been returned to physicians within 10 days in medically urgent situations. With preauthorization, many insurance providers cover the cost to sequence a child and both parents. If not, the out-of-pocket fee runs $6,650.”
“All families deserve a clear diagnosis of their child’s condition,” added Dr. Wayne Grody, director of the UCLA Clinical Genomics Center and a professor of pathology, human genetics and pediatrics at the David Geffen School of Medicine and Mattel Children’s Hospital UCLA. “Exome sequencing plays an important role in identifying the precise cause of a child’s illness. This is immediately useful to families and physicians in understanding how the disease occurred, preventing unnecessary testing, and developing the best strategies to treat it.”
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