Whole-exome sequencing holds promise for complex disease

Until recently, genetic testing was limited to diagnosing, predicting and treating relatively rare monogenic (mendelian) disorders, such as familial adenomatous polyposis and hereditary hemochromatosis. Polygenic (complex) diseases — the kind most commonly seen in clinical practice — were beyond the scope of first-generation sequencing technologies.

But next-generation sequencing (NGS) now makes it possible to explore the genetic etiology of polygenic (complex) diseases — those resulting from a mix of several genetic variants and environmental triggers.

"NGS offers rapid sequencing of the entire human genome compared to traditional molecular testing that focuses on a single gene at a time. And it does so at low cost with high accuracy," explains Konstantinos N. Lazaridis, M.D.

The majority of disease-causing mutations occur in the 1.7 percent of the human genome known as the exome, so at present NGS is used, in clinical applications, to assess only protein-coding genes. This can be especially useful with patients for whom testing of individual genes failed to make a diagnosis.

Dr. Lazaridis notes, "In the past, GI patients would come to us, and if we were thinking about familial testing, we would send out a specimen to look for a specific gene. If the test came back negative, there would be no further follow-up. Now we have the ability to integrate whole-genome or whole-exome sequencing into patient care. This global approach goes far beyond single-gene testing."

Another clinical application for NGS is targeted sequencing for gene panels of a specific disease, such as hereditary colon cancer. In this process, certain capture strategies are used to enrich subsets of genes or exons, allowing more accurate detection of variants.

Individualized Medicine Clinic

At all Mayo Clinic campuses, GI patients needing genetic testing now can be referred to an Individualized Medicine Clinic, which offers whole-exome sequencing for advanced metastatic cancer and diagnostic odyssey cases — people with early-onset disease, syndromic disorders of unknown etiology or a family history suggesting a genetic basis for illness. Within these parameters, patients are screened and accepted on a case-by-case basis.

Dr. Lazaridis points out that because it can take several months to receive test results, DNA sequencing is not for people for whom time is of the essence, even though cancer patients who undergo it are likely to have exhausted all proven treatment options.

Limitations and challenges

Although NGS promises a personalized approach to complex diseases, it has limitations and, like genomics in general, raises legal, ethical and social questions. Counseling is provided before, during and after genetic testing, for instance, but the effect of unexpected findings on patients and families is unclear. Dr. Lazaridis further notes that at present, only about 25 percent of whole-exome testing will provide clinically relevant findings. "Experience, scientific progress and time will facilitate these efforts going forward," he says.