Whole-exome sequencing will be new standard for genetic testing

The majority of disease-causing mutations occur in the exome — the 1.7 percent of a human genome that encodes proteins. Thus, whole-exome sequencing (WES) is likely to produce a higher yield of relevant variants at far lower cost than whole-genome sequencing is.

Douglas L. Riegert-Johnson, M.D., a gastroenterologist and medical geneticist at Mayo Clinic's campus in Jacksonville, Florida, calls the exome "the pay dirt" of genetic testing because the cost is relatively low and the yield relatively high.

Still, the translation of the vast amounts of information generated by whole-exome sequencing — a file size of 5.7 gigabytes — into medically useful information is in its infancy, literally and figuratively. Most of the current applications involve children who have undiagnosed conditions most often related to seizures, developmental delay and other neurological conditions.

In 2010, physicians at the Children's Hospital of Wisconsin and the Medical College of Wisconsin sequenced the exome of a 4-year-old boy with a severe and previously undescribed intestinal disorder. Sequencing revealed he had X-linked lymphoproliferative syndrome (XLP). The cord blood transplant that resolved the XLP also seemed to resolve the boy's gastrointestinal symptoms.

Since then, many other children have undergone exome sequencing in the U.S. and elsewhere. In 2015, Spanish researchers used exome sequencing to identify a new gene associated with autosomal recessive retinitis pigmentosa, a group of progressive inherited retinal dystrophies. In the same year, scientists at the Translational Genomics Research Institute (TGen) in Phoenix sequenced the genes of six pediatric patients with neuromuscular disease, identifying disease-causing variants in the CACNA1S, RYR1 and COL6A3 genes. All the children had undergone years of unproductive tests before enrolling in TGen studies.

The future of WES

Still, these stories are the exception. Only about 25 percent of whole-exome testing yields clinically relevant findings in children — the population with the highest yield. "Most people will not find a cause for their symptoms," Dr. Riegert-Johnson says. "In those who do, medical management may change but usually not."

In 2012, one of Dr. Riegert-Johnson's patients was in the first group of adults to undergo exome sequencing outside a research setting. The results were inconclusive.

Still, Dr. Riegert-Johnson believes in the widespread future potential of exomic testing. "In the next five to 10 years, as costs continue to come down, results are obtained in a more timely fashion and interpretation is more established, it will replace other types of genetic testing. Instead of testing for specific cancer genes, we will just use exomic testing," he says. "We are halfway there now. We used to just test for BRCA1 and BRCA2, for instance. Now, we rarely order one gene at a time. Rather, it's a panel of 10, 12 or 23 genes. The breast cancer panel has gone from one gene to 23. It's not much of a jump from 23 to 100."

A similar change has occurred in Mayo's colon cancer genetic panel, which has grown from a single gene to 14 — a number that will continue to increase.

Eventually, gene sequencing is likely to move beyond cancer testing and diagnostic odyssey cases to include predictive testing from birth. Four NIH-funded projects looking at different aspects of gene sequencing in healthy newborns are already underway.

Dr. Riegert-Johnson stresses that the main drivers are lower costs and faster turnaround times. Mayo Medical Labs is developing its own exome test that returns results in 90 days. "It used to take 303 days," Dr. Riegert-Johnson says. "It's gotten better since then."