July 1, 2014 (Vol. 34, No. 13)

Although whole-exome sequencing (WES) has its limitations, particularly with respect to secondary or incidental findings, it may still shine in routine clinical care, particularly if testing is contingent on specific indications and focuses on primary findings. That is, WES, applied judiciously and with circumspection, may prove invaluable in a number of scenarios.

Already, WES seems helpful to patients who have endured uninformative diagnostic odysseys, or who suffer conditions characterized by genetic heterogeneity—the involvement of a large number of genes. In cases where serial genetic testing poses steep costs, a WES test may seem economical, despite carrying a price tag of a few thousand dollars.

In any event, economy could be conceived more broadly, encompassing the costs that accompany delays in diagnosis, which include patient stresses related to uncertainty or the inability to make plans. There is also the dread of awaiting invasive diagnostic procedures.

WES does seem an attractive option, one that is increasingly available through clinical laboratories. Still, few studies have evaluated WES in clinical settings. A new study, however, has been completed by a team of geneticists at Columbia University. These geneticists performed WES for clinical diagnostic purposes in 115 patients, most of whom had indications of birth defects or developmental delay. In 32.1% of the cases, the geneticists identified a definitive genetic etiology.

The geneticists, led by Wendy K. Chung, M.D., Ph.D., published their results June 5 in Genetics in Medicine, in an article entitled “The usefulness of whole-exome sequencing in routine clinical practice.” The authors indicated that their experience could assist other clinicians in implementing WES into their clinical practice, particularly with respect to practicalities such as patient education in pretest counseling, consent, insurance coverage, turnaround time, yield of testing, updates of test results, and impact on clinical care.

On previous occasions, Dr. Chung has been frank about the limitations of WES:

  • Many variants, even in causative genes, are novel and the association with the disease is unknown or unclear.
  • Some variants may be in genes whose function is unknown.
  • Functional follow-up is required to determine if the variant affects the protein and is causative.
  • About 50% of families who should have identifiable mutations lack them.

Nonetheless, in the current article, Dr. Chung and her colleagues are clear that “WES is feasible; has clinical usefulness; and allows timely medical interventions, informed reproductive choices, and avoidance of additional testing.”

Specific results from the study included the identification of four new candidate human disease genes and possibly expanded the disease phenotypes associated with five different genes. Establishing a diagnosis led to discontinuation of additional planned testing in all patients, screening for additional manifestations in 8, altered management in 14, novel therapy in 2, identification of other familial mutation carriers in 5, and reproductive planning in 6.

To return to the issue of yield, the authors indicated that their figure of 32.1% should be considered the lower bound of clinical sensitivity for exome sequencing: “Improvements in sequence coverage, sequence alignment, variant calls, copy-number variant detection, predictions of pathogenicity, increasing number of human disease genes identified, and possibly whole-genome sequencing will only improve the diagnostic yield of genomic testing.”

Good Enough for Now

The authors are clearly disinclined to let the perfect be the enemy of the good. Besides asserting that WES is already of demonstrated utility and likely to improve, the authors also noted that they were largely successful in obtaining insurance coverage for most or all of the cost of WES.

“Expanded use of WES will help us tailor medical management, anticipate associated medical problems, avoid expensive and sometimes invasive tests, accurately predict the risk of recurrence for parents and other family members, and accurately identify other family members carrying the mutation in order to enable preventative medical care and reproductive planning,” continued the researchers. “Provision of accurate prognostic information, although not medically actionable, was used by families to obtain the appropriate social services and educational services and was personally actionable as they made personal and financial plans based on the prognosis.”

The researchers concluded that WES is an effective tool to diagnose genetically heterogeneous disorders in a clinical setting, especially in young children in whom all the clinical features may not yet be evident. They also emphasized that WES is valuable in providing evidence for possible expansion of the phenotypes associated with recognized human diseases and to identify new candidate genes associated with human disease.

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