Diagnostic Yield of Exome Sequencing Consistent; Targeted Implementation Could Improve True Value

Whole-exome sequencing is permeating clinical practice, particularly for evaluation of pediatric patients with neurological conditions and developmental delay. Two recently published studies show remarkable similarity in the diagnostic yield associated with clinical exome sequencing (CES); however, questions remain regarding the contexts in which the modality would be most cost-effective to implement. While exome-scale sequencing may reduce testing costs, compared to multiple, sequential genetic tests undertaken as part of a diagnostic odyssey, efforts are under way to define the circumstances for which CES will be economically beneficial, clinically useful, and have “personal utility” for patients and their families. “Establishing the mechanism of an individual’s disease has scientific value and satisfies intellectual curiosity, but can also have substantial personal utility for patients and their families,” according to an editorial by Jonathan Berg, M.D., Ph.D., from the University of North Carolina at Chapel Hill, accompanying the two studies in the Oct. 18 issue of theJournal of the American Medical Association. “The personal utility—both positive and negative—afforded by such information, although potentially measurable . . . would be difficult to calculate . . .  in a traditional economic sense. Because these studies focus on the molecular diagnostic yield from a clinical laboratory perspective, the effect of such diagnoses on the patients and their families are justifiably beyond their scope, but will ultimately be critical in determining how best to implement widespread clinical exome sequencing.” Berg calls the two studies “compelling” in their demonstration that CES can establish molecular diagnosis. In both cases neurological disorders or developmental delay were the most common reasons for referral and the majority of patients were pediatric. These studies begin to elucidate commonalities that may aid future efforts in defining effective implementation of CES. In the first study, conducted at Baylor College of Medicine (Houston), the researchers conducted analysis on the CES results of 2,000 consecutive patients (88 percent pediatric patients analyzed between June 2012 and August 2014). After excluding low-quality variants, an average of 875 variants per sample were analyzed. A molecular diagnosis was possible for one-quarter of the patients, including diagnostic mutations not previously reported (58 percent of the diagnoses). The lowest diagnostic yield was seen in the nonneurological group (20.1 percent), while the highest yield was seen in the specific neurological group (including ataxia, movement disorder, and spastic paraplegia; 36.1 percent). “For the 25 percent of cases that received a molecular diagnosis, this information ended the diagnostic odyssey, provided more informed medical management, and allowed for precise determination of reproductive risks; however, relatively few cases resulted in specific treatment to reverse the condition,” acknowledge the authors, led by Yping Yang, Ph.D. In the second study, a group of researchers from the University of California, Los Angeles, conducted CES on 814 consecutive patients (64 percent pediatric; 37 percent developmental delay) with undiagnosed, suspected genetic conditions (January 2012 and August 2014). The overall molecular diagnosis rate was 26 percent in this cohort. However, in this study trio-CES was performed for half of patients, in which both parents were also sequenced. The researchers found that the molecular diagnosis rate for trio-CES was significantly higher, reaching 31 percent. Among the 127 trio cases with a conclusive molecular diagnosis, half had a de novo variant, 20 percent had a compound heterozygous variant, 16 percent had a homozygous variant, and 8 percent had an X-linked hemizygous variant. “The trio-CES test has the potential benefit of permitting more sensitive identification of de novo variants and compound heterozygotes and removing from consideration the many heterozygous rare variants observed in each exome from being considered causal in the affected individual because transmission is observed from an unaffected parent,” write the authors, led by Hane Lee, Ph.D. “This has not been routinely implemented by other centers due to costs and potential concerns for incidental findings in the unaffected parents.” “Clinical genome-scale sequencing clearly has the potential to become a cost effective strategy to end an expensive and difficult diagnostic odyssey for some patients,” writes Berg. “More data are needed to demonstrate whether this is broadly true and in which contexts exome sequencing will be most useful. . . . Research is required to formally establish the clinical utility of genetic testing by systematically measuring not just changes in management but also long-term outcomes.” Takeaway: CES is providing definitive molecular diagnoses for roughly one-quarter of cases. But by refining use to certain specific phenotypes and broadening testing to trios (including the parents of cases), diagnostic yield may be closer to one-third, further improving the cost-effectiveness of CES. Side Box: Results of Sequencing at Baylor The following is a breakdown of some of the molecular results from 2,000 cases of whole-exome sequencing at Baylor. Of the 504 cases with a molecular diagnosis:

• 708 presumptive causative variant alleles were identified.
• 53.1 percent had an autosomal dominant Mendelian disease pattern.
• 30 percent had mutations in disease genes reported since 2011.
• There were 95 medically actionable incidental findings (unrelated to the referral phenotype), including 59 patients with mutations recommended for reporting by the American College of Medical Genetics and Genomics.
• Reporting time per case review was approximately seven hours (down from 18 hours per case during the initial implementation period).