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Reanalysis of Clinical Exome Data Over Time Could Yield New Diagnoses

NEW YORK (GenomeWeb) – Clinical exomes that are re-evaluated in a systematic way could yield new diagnoses and prove useful to clinicians, according to a study published yesterday in Genetics in Medicine.

A team of researchers from Stanford University set out to examine whether nondiagnostic clinical exomes could provide new information for patients if they were re-examined with current bioinformatics software and knowledge of disease-related variants as presented in the literature.

Clinical exome sequencing yields no diagnosis for about 75 percent of patients evaluated for possible Mendelian disorders, wrote senior author Gill Bejerano and his colleagues. But a reanalysis of exome and phenotypic data from 40 such individuals using current methods identified a definitive diagnosis for four of them — 10 percent — the team said.

In these cases, the causative variant was de novo and found in a relevant autosomal-dominant disease gene. At the time these exomes were first sequenced, the researchers wrote, the existing literature on these causative genes was either "weak, nonexistent, or not readily located." When the exomes were re-examined by his team, Bejerano noted, the supporting literature was more robust.

The researchers looked at the four cases to see when their clinical exome reports were generated and when the causal variants were first reported in the literature. They also checked to see whether the variants were reported in the Online Mendelian Inheritance in Man (OMIM) database and the Human Genome Mutation Database (HGMD) Pro 2015.2, "to quantify the growth in gene-disease and variant-disease associations."

The first of the four patients had a clinical exome report generated in July 2012, but the first publication linking her disease to a specific gene was not published until August 2012. A June 2015 report identified the variant as the presumed cause of the same condition in an unrelated male, the team wrote. The variant is not currently listed in the HGMD Pro 2015.2.

The second patient's exome report was generated in November 2013. Although there had been case studies reporting connections between her condition and a specific gene variant in December 2010 and November 2012, the definitive report linking the disease to the gene was not published until May 2014, the team wrote. That variant is also not currently listed in the HGMD Pro 2015.2.

In the third case, the patient's disease and the causative gene were linked in the literature before the patient's exome was generated — May 2014 and September 2014, respectively. The variant was also added to the HGMD database after publication.

And in the fourth case, the patient's exome report was generated in October 2012, but the link between his disease and a specific gene variant wasn't identified in the literature until July 2013. It was soon thereafter added to the HGMD database.

The team also tracked the growth of the OMIM and HGMD databases, noting that since 2004, the number of OMIM disorders with a noted molecular basis has increased at an average rate of 266 entries per year, and that the HGMD database has an average growth rate of 9,210 variants and 241 genes per year.

"Approximately 250 gene-disease and 9,200 variant-disease associations are reported annually. This increase in information necessitates regular re-evaluation of nondiagnostic exomes," the team wrote. "To be practical, systematic reanalysis requires further automation and more up-to-date variant databases. To maximize the diagnostic yield of exome sequencing, providers should periodically request reanalysis of nondiagnostic exomes."

Indeed, various teams of researchers at the American College of Medical Genetics and Genomics annual meeting in March reported on their own strategies for boosting the diagnostic rate by reanalyzing exome data and using matchmaking tools to find similar cases.

At the time, Baylor College of Medicine researcher Pengfei Liu told GenomeWeb that while re-analysis increased the diagnostic rate for two cohorts to only 30 percent and 36 percent from 25 percent, he believed that the rate at which new disease genes are discovered has not plateaued yet, meaning more diagnoses could emerge from data re-analyses over time.

"It takes 40 to 100 hours for highly trained staff to throw an exome. The exome solve rate is 25 percent now, but was 10 percent for quite a while. There are tens of thousands of negative exomes out there. Each cost upwards of $7,000," Bejerano told GenomeWeb. "The fact that 10 percent of them are likely solvable using new tools and knowledge (and without need for patient re-evaluation) is [very important] for the patients, their families, even fiscally."