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Clinical Exome Reanalyses Lead to New Molecular Diagnoses

NEW YORK (GenomeWeb) – Members of a team led by investigators at the Baylor College of Medicine and Baylor Genetics have illustrated the sharp rise in molecular diagnoses that can be achieved by reanalyzing clinical exomes sequenced several years ago.

As they reported in a correspondence article in The New England Journal of Medicine, the researchers began by reanalyzing the first 250 individuals assessed by clinical, proband-only exome sequencing at the Baylor College of Medicine's CLIA- and CAP-certified clinical diagnostics laboratories in 2011 and 2012 — a cohort described in a 2013 paper in NEJM —before stretching their reanalyses to another 2,000 cases sequenced consecutively in 2012 and 2013.

In each cohort, they saw significant increases in molecular diagnostic yields after manual or semi-automated reanalyses. And with survey responses from nearly two-dozen health care providers, the investigators got a sense of strategies being used to convey new diagnoses insights to patients, as well as the consequences of the reanalyses.

"Education is necessary for physicians and patients to understand the concept of an 'evolving' molecular interpretation," corresponding author Pengfei Liu, a molecular and human genetics researcher at the Baylor College of Medicine and laboratory director of clinical research at Baylor Genetics, and his colleagues wrote.

In particular, the authors concluded that "periodic, cost-effective reanalysis may benefit patients and their families and physicians, although an important caveat is that our study was not designed to measure the clinical benefit of the intervention."

For the initial reanalysis outlined in NEJM today, the researchers manually reanalyzed 250 cases, raising the molecular diagnostic yield to nearly 47 percent — up from less than 25 percent when that clinical exome set was first evaluated.

Using that data, they then designed a gene prioritization method for subsequent semi-automated analyses of another, larger historical exome set. Across that set of 2,000 cases, the team saw a slightly more modest rise in the molecular diagnostic rate, from just over 25 percent initially to almost 37 percent after a semi-automated reanalysis.

"We did not carry out manual reanalysis of the exome sequences of the second, much larger cohort, given the burden of the task," the investigators explained. "Potential factors contributing to the differences in overall diagnostic yields between the two series … include different percentages of patients with Mendelian disorders and a difference in sensitivity between comprehensive manual analysis and semi-automated analysis."

When the team reached out to health care providers for 64 of the individuals who were newly diagnosed after exome reanalyses, it got survey results for more than half of the providers representing 66 percent of those patients.

Of those, 13 of 23 health care providers pointed to a need for the ordering physician to receive reanalysis results, while the remaining 10 health care providers suggested that all physicians on the patient's care team should be informed of new diagnoses uncovered by reanalysis.

The survey suggested that roughly three-quarters of the patients got additional genetic counseling after reanalysis, while 17 of the 64 patients had a clinical management change that was spurred on by new molecular diagnostic clues in their exomes.

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