NEW YORK (GenomeWeb) — After more than three years offering clinical whole exome sequencing for pediatric and adult patients suspected of having rare genetic disorders, clinicians from Columbia University Medical Center have concluded that the approach is a feasible, useful, and timely option for routine clinical assessment of such patients.
The group published a study this month in Genetics in Medicine reviewing data from all patients who received whole exome sequencing (WES) at the center between 2011 and 2013.
According to the authors, though exome sequencing is not yet an appropriate first choice for all patients, it significantly improved the group's diagnostic ability. The study also suggested that sequencing can result in more timely medical intervention and thus avoid costly and lengthy diagnostic odysseys for patients with unexplained genetic disorders.
"Our results confirm that [comprehensive sequencing] gives the opportunity, besides making diagnosis and handling patients, to find things that were completely unexpected and unknown. That's something there is no other way to find," Alejandro Iglesias, the study's first author, told Clinical Sequencing News.
Iglesias is one of three CUMC geneticists whose patients received WES during the study period. In their review, he and his colleagues mined records from a total of 115 patients who received WES through the center up to July 2013.
Unlike other studies of WES in the context of clinical research, the Columbia group's data comes out of a purely routine clinical genetics practice. The three doctors at the center decided to refer patients for WES on a case-by-case basis, they reported, sending samples to be analyzed by the Columbia University Laboratory of Personalized Medicine, Ambry Genetics, GeneDx, or Baylor College of Medicine.
According to Iglesias, most patients in the study had already had other genetic testing, such as single-gene or microarray-based multiplex mutation tests, prior to having their whole exomes sequenced. Moving forward, he said, most patients are still likely to get more targeted testing first at Columbia, especially because WES still lags behind less comprehensive methods in its turnaround time.
During the study, most of the laboratories returned patient WES results within an average of four months, while Ambry averaged closer to six months, the authors wrote.
However, Iglesias said, the study also suggested that WES can avoid longer and costlier testing odysseys, and in some cases improve patient treatment or outcomes by identifying an effective therapy earlier.
Because of this, he said the Columbia genetics practice is at a cusp where it is starting to make sense to turn to exome sequencing earlier in the search for a genetic cause of disease or even as a first-line approach.
In the study, Iglesias and his colleagues found that of the 115 cases reviewed, whole exome sequencing yielded a definitive diagnosis in 37 individuals, or about 32 percent. According to the authors, this performance is similar or slightly higher than what other clinical exome sequencing studies have reported.
Among the results of the study, the team found that two patients had mutations in two separate genes that were diagnostic of two separate co-existing conditions. Sequencing identified de novo mutations in 15 cases and identified four novel candidate disease genes, the authors wrote. Results also suggested that the phenotypes of five clinical conditions might be expanded.
In two subjects, exome sequencing did not provide a diagnosis initially, but the patients were later found to have a causative mutation after genes for their diseases were reported in the literature. This posthumous diagnosis would not have been possible without the availability of WES results, according to the authors.
"Because the genetic literature is rapidly changing as new genes are identified for human disease, it is critical that laboratories maintain a database of the variants identified for patients and reassess the significance of these variants over time," they wrote.
Iglesias said that diagnosing genetic conditions doesn't always mean that the diagnosis influences treatment or outcomes. In many cases, the best result that exome sequencing or any genetic testing can offer is an answer to why a child has a certain phenotype or symptom.
But, he said, the group did see some cases in which a diagnosis by exome sequencing led to specific interventions and impacted patient care.
"We didn’t look in too much detail, but definitely for a few of these patients, the whole thing makes a difference," Iglesias said.
"Sometimes you hear the argument that treatments after sequencing aren't different than what you would be doing anyways," he added. "This can be true, but the big difference is that now you know what the problem is and before you didn't. And some times there are things you can do for the patient that before you didn't have any clues."
In the Columbia cohort, exome sequencing-based diagnosis of a GPT2 mutation lead to the use of pyridoxine vitamin B6 in three siblings, the authors wrote. Identification of a mutation in the gene SCN1A in a patient with a Dravet-like phenotype also led to tailored antiepileptic treatment. In several cases, definitive diagnosis by exome sequencing saved patients from additional invasive testing such as muscle biopsies, or determined eligibility for a clinical trial.
The researchers also reported that diagnoses also offered prognostic information that families used to obtain social and educational services, or to make financial or family planning decisions.
Overall the authors reported that exome sequencing allowed the clinicians in the study to discontinue further interventions in all diagnosed patients, to screen for other disease manifestations in eight of them, to alter clinical management in 14, to change treatment in two, to identify other family mutation carriers in five, and to assist with reproductive planning for six families.
Insurance paid for WES for the majority of the patients, the group wrote, with 90 percent of those on private insurance and 80 percent of those with Medicaid covered. Medicare coverage was not provided for any of the contracted labs, so one patient on Medicare paid for sequencing out of pocket, the group wrote.
Iglesias said that the clinicians involved in the study expect to continue to expand their use of whole exome sequencing. Though the study did not quantify the financial, medical, or other benefits of WES over other techniques, he said that it at least hinted at some of these factors while demonstrating the approach to be diagnostically accurate and sensitive.
"The bottom line is that higher suspicion of a genetic condition is what usually goes along with a positive result, so, so far we are not using this a first-line test," he said. "From the point of view of cost-benefit and speed, it's cheaper and it's faster right now to do microarray or other testing. It gives you a good amount of information, and sometimes that works, and you don't have to go after something else."
But the flip side, he added, especially in light of the team's review, is that it seems clear that for some cases who might go on to months or years of targeted tests, it might be better from both a cost and efficiency standpoint to cut to the chase and just sequence the whole exome.
"At this point I would say we are somewhere in the middle," he said. "Sometimes you get to the point where you have to make a decision whether it's worth it to keep trying with individual tests or jump into this. You start thinking about all the things you might be doing, how much time you might spend and how much money it might cost, or stress [it might impose on the family]."
The researchers didn’t deal with incidental findings in the study, but Iglesias said that the center has taken an opt-in, opt-out approach. Patients can avoid hearing about all incidental findings, or opt-in to learn about actionable findings if they prefer. Iglesias also said the group would provide raw data to patients who desire it.