Periodic Exome Reanalysis Yields New Diagnoses

Reanalysis of clinical exome data at a two- to three-year interval could result in an incremental 10 percent diagnostic yield, according to a study published online July 21 in Genetics in Medicine. The authors offer some practical suggestions for laboratories evaluating the cost-benefit of the time, labor, and expense associated with reanalysis versus the incremental gain in understanding of variant-disease associations reported each year.

A 25 percent diagnostic yield for clinical exome sequencing of patients with presumed Mendelian disorders has been previously reported. However, approximately 250 new, gene-disease and 9,200 variant-disease associations are reported annually, the authors say.

In the present study raw exome (pro-band only) and phenotypic data of 40 individuals with previously nondiagnostic clinical exomes were reanalyzed with current software (ANNOVAR, version 527, to annotate variants) and literature for each candidate causative variant. Overall, the majority of participants were female (n=25), 10 years of age or younger at the time of initial sample collection (n=31), and had a neurologic or neurodevelopmental condition (n=28). On average, the initial clinical exome reports were issued 20 months before reanalysis.

The researchers made a definitive diagnosis for 4 of the 40 participants—a causative, de novo variant in a relevant autosomal-dominant disease gene. At the time of the initial clinical exome reports, the literature to tie the causative genes to the participants’ phenotypes was weak, nonexistent, or not readily located and the variant was not listed in the report. But at the time of diagnosis by reanalysis, the supporting literature was 1 to 3 years old.

The authors say that the growth in the literature is exemplified by case 1, who was issued a nondiagnostic exome report on July 25, 2012. However, the first paper linking the de novo mutation to the condition was published two weeks after the report—in August that year. The data was added to the Human Genome Mutation Database the same day as publication.

“Yet, nearly three years later, the patient remained undiagnosed,” write the authors, led by Aaron Wenger, Ph.D., from Stanford University in California. “This illustrates the great need to regularly reevaluate nondiagnostic exomes in light of updated knowledge to maximize diagnostic yield.”

Some clinical laboratories do reanalyze exomes upon a provider’s request, the authors acknowledge, but may limit reanalysis requests to one per year or require a fee for reanalysis. The cost-benefit calculation for more frequent reanalysis could be shifted with increased automation; the ordering of trio exomes; and requests for providers for reanalysis that include an update on the patient phenotype.

“Frequent reevaluation of exomes is challenging in practice because of the required labor,” writes Wenger and colleagues. “Larger studies may be helpful to define a standard practice for the timing of reanalysis, taking into account the cost of reanalysis and the evolving rate of discovery of gene-disease relationships.”

Takeaway: Periodic, systematic reanalysis of clinical exome data may yield relevant additional diagnoses based on improvements in variant understanding in the interim time. Ideal time for reanalysis requires further study.