Next-generation sequencing may reduce cost and wait time for some genetic diagnoses: Experts argue that clinical evaluation remains crucial
Article first published online: 19 NOV 2013
DOI: 10.1002/ajmg.a.36349
© 2013 Wiley Periodicals, Inc.
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Next-generation sequencing (NGS) may speed some genetic diagnoses and save money, but it is a tool best used by an experienced clinician guided by a patient's clinical presentation and previous workup, according to a recent study.
That's because geneticists often diagnose inherited conditions without NGS—which includes advanced methods that can retrieve data from hundreds of genes at once—or results from older genetic tests.
Researchers from Duke University in Durham, North Carolina did a retrospective review of 500 unselected, consecutive pediatric and adult cases seen at a Duke University Medical Center genetics clinic. Of the 500 patients, 46% were diagnosed by either clinical evaluation alone or an evaluation followed by targeted genetic testing at Duke. An overwhelming majority (72%) of these patients received a diagnosis at their first visit to the clinic, without any genetic testing, write researchers in a recent Genetics in Medicine article [Shashi et al.,2013].
Obtaining a genetic diagnosis for a patient who had to return for subsequent visits cost them an estimated $25,000, a figure that includes genetic tests [Shashi et al., 2013]. An earlier study of a whole-exome sequencing (WES) pilot program conducted at Duke produced a diagnostic yield of 50% [Need et al., 2012]. Shashi et al referred to that study to estimate that using NGS after the first clinical visit could save about $5,000 per patient.
While the current paper stresses these cost savings, it also emphasizes the importance of geneticists' clinical skills. “Any test, including next-generation sequencing, is only as good as the clinician ordering and interpreting it,” says the study's co-author and genetic counselor Allyn McConkie-Rosell, PhD, Associate Research Professor at Duke University School of Medicine in Durham, North Carolina.
Figure 1. Test results from next-generation genetic sequencing, which retrieves data from hundreds of genes at once, may yield more specific diagnoses for patients who have had nonspecific and unusual presentations of genetic diseases. Darryl Leja, National Human Genome Research Institute
Expanded Use for Exome Sequencing
The researchers conducted the current study with an eye toward possibly using genomic sequencing at their institution, and because they found insufficient published data on diagnostic outcomes for traditional testing technologies, including microarray.
“We felt it critically important to know [how] traditional testing technologies, including microarray, are performing in the clinical setting before expanding to whole-exome and whole-genome sequencing,” explains first author Vandana Shashi, MD, Associate Professor of Pediatrics at Duke University School of Medicine.
For the study, Dr. Shashi and her colleagues looked at the reasons that patients came to the clinic. If patients did not receive an immediate diagnosis, the researchers determined the type and number of tests given, and the cost of tests needed to produce a subsequent diagnosis.
The most common single reason for referral to the genetics clinic was developmental delay, with 50 such cases, followed by malformations, and family history of a disease. Questions about a specific diagnosis and various other concerns spurred additional referrals, the researchers noted.
The 46% of patients in the cohort who received a diagnosis on the initial visit frequently had single gene disorders, researchers say. However, they did not break down the type of diagnoses made at the first visit, according to Dr. Shashi.
Cost Differential
Shashi et al found a substantial difference in the actual cost of genetic tests performed at Duke for undiagnosed patients versus patients who were diagnosed.
For undiagnosed patients, the mean testing cost was $4,721, with the most expensive case totaling $30,438. For diagnosed patients, the mean cost was $3,285, with most expensive case totaling $15,037. These figures do not include non-genetic lab test or genetics evaluations, so the actual total cost of diagnoses may be much higher, says Dr. Shashi.
A Question of Yield
The diagnostic yield estimate of 50% by Shashi et al is realistic, say some geneticists, but others call for additional studies.
Michael Bamshad MD, Professor of Pediatrics at University of Washington School of Medicine in Seattle, argues the estimate warrants empirical validation because the earlier study by Need et al on which it's based included just 12 patients with congenital anomalies, intellectual disabilities, or both. In addition to its small size, the patient mix studied by Need et al may differ from what is seen in particular genetics clinics, Dr. Bamshad adds.
Anita Rauch, MD, Professor and Chair of Medical Genetics at the University of Zurich in Switzerland, says the 50% figure is close to the 55% diagnostic yield she found when using WES in 51 Swiss and German children who all had severe intellectual disability [Rauch et al.,2012].
However, sequencing depth may affect yield and cost-effectiveness. Dr. Rauch notes that a similar study of 100 children with intellectual disability by a Dutch team found only a 16% yield, but researchers didn't sequence as deeply [de Ligt et al., 2012].
Additionally, Shashi et al note that the effectiveness of NGS is limited because it cannot detect trinucleotide-repeat disorders, mitochondrial DNA mutations, or disorders of epigenetic regulation.
Meanwhile, research from Baylor College of Medicine, published after the Shashi et al paper, agrees with the Duke researchers that WES may yield more diagnoses for patients with nonspecific and unusual presentations of likely genetic disease. However, that study of 250 patients on which WES was used had an overall diagnostic yield of 25%, half of the Duke figure [Yang et al., 2013].
Many genetics clinics are now considering how to best “integrate whole-exome sequencing into diagnostic pipelines,” Dr. Bamshad notes. But because the authors didn't look at the cost of exome sequencing in a large group, “their suggestions remain to be tested,” he adds.
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