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Trio Analysis in Genetically Heterogeneous Disorders Improves Dx Yield of Whole-Exome Sequencing

NEW YORK (GenomeWeb) — In a study of the clinical applications of whole-exome sequencing (WES), researchers at GeneDx and Columbia University have found that the analysis of trios can significantly improve the testing's diagnostic yield.

The team performed WES on 3,040 cases over the course of three years for a variety of clinical indications — in 76 percent of the cases, the proband was tested with two or more family members, the team reported yesterday in Genetics in Medicine.

While the overall diagnostic yield of WES was 28.8 percent, the team wrote, it was 23.6 percent in proband-only cases, and rose to 31 percent in trio cases. In fact, the yield was more than 50 percent for certain clinical indications. Patients who saw the highest yield had disorders involving hearing, vision, the skeletal muscle system, the skeletal system, multiple congenital anomalies, skin, the central nervous system, and the cardiovascular system.

Further, the researchers found that 8.3 percent of the cases included a candidate gene that has since been found to be disease-causing. And many of the cases expanded the phenotypes of previously described conditions. "Of 2,091 cases in which secondary findings were analyzed for 56 American College of Medical Genetics and Genomics–recommended genes, 6.2 percent had reportable pathogenic variants," the team added. "In addition to cases with a definitive diagnosis, in 24.2 percent of cases a candidate gene was reported that may later be reclassified as being associated with a definitive diagnosis."

This study shows that the usefulness of WES as a diagnostic tool is greatly increased when the family of the proband is available for testing, said senior author and GeneDx co-founder Sherri Bale. "One of the most exciting things about whole-exome sequencing is that it has allowed us to very rapidly, almost exponentially, identify genes that are related to human disease that we didn't know before. This keeps happening faster and faster, more and more."

And although this study focused on 3,000 cases, GeneDx has performed WES on more than 10,000 families — more than 30,000 exomes, added Marc Grodman, CEO of GeneDx parent company BioReference Laboratories. "In more and more of these cases, we can come up with answers, and in certain conditions at a very high rate. We've shown that perhaps we can cut the diagnostic odyssey a bit shorter and provide answers."

Further, Grodman said, this study and GeneDx's work shows the efficacy of genomic medicine. "It is our mission to do this [type of testing] responsibly, so that it's used on those who need it the most," he added. "And when we do that, we start to show that this will have not only the greatest clinical value, and the most value for patient care, but also provide the most cost-effective solution."