COLD SPRING HARBOR, NY (GenomeWeb) – Encouraged by their success in applying whole-exome sequencing to diagnose rare Mendelian diseases in the pediatric population, researchers at the Baylor College of Medicine are now turning their attention to clinical exome sequencing outcomes in adults.
Speaking at the annual Biology of Genomes meeting here yesterday, Richard Gibbs, director of Baylor College of Medicine's Human Genome Sequencing Center, provided an overview of recent results from Baylor's clinical exome sequencing program, which has largely focused on Mendelian cases in children so far.
Gibbs also shared a glimpse at efforts underway to try out the same diagnostic exome sequencing strategy for finding high-impact, high-penetrance mutations in adults — an approach that appears to have a diagnostic rate approaching 20 percent based on results from the group's pilot projects.
When investigators first considered taking genomics into the clinic several years ago, Gibbs recalled, cancer diagnoses and treatment seemed like obvious places to start. But because of the complexity and heterogeneity of tumors, such clinical translation was also daunting.
Instead, the Baylor team decided to tackle pediatric Mendelian disorders when setting up its initial clinical sequencing program. Together with Baylor's Medical Genetics Laboratories, the genome center established a CLIA-certified Whole Genome Laboratory (WGL) that in 2011 began offering clinical exome sequencing tests for children with unexplained genetic disorders such as intellectual disability or autism.
Around 6,000 or so clinical whole exomes have been sequenced at the WGL to date, Gibbs noted. He and his colleagues reported on results for 2,000 of those cases — tested consecutively between June 2012 and August 2014 — in the Journal of the American Medical Association late last year.
In that paper, the team demonstrated that it could make a molecular diagnosis in roughly 25 percent of cases with exome sequencing, though the diagnostic rates varied somewhat depending on the phenotypic category considered.
In nearly 60 percent of the 504 cases diagnosed in that study, researchers narrowed in on diagnostic mutations that had not been described previously. They also saw a preponderance of de novo genetic glitches not found in either parent.
Along with these diagnoses, researchers are tapping into the exome sequencing results to uncover new disease genes, get a clearer picture of how some Mendelian diseases are passed down, and expand the features and symptoms associated with certain conditions.
Preliminary results from other studies suggest the diagnostic rate for whole-exome sequencing-based tests is only slightly lower in adults, Gibbs noted, coming in at over 17 percent.
Again, de novo mutations got the disease blame in most of the adult cases tested so far — around 86 percent — though the team suspects they may be missing some de novo alterations owing to the absence of available parental samples in many adults.
For example, investigators have done exome sequencing on samples from around half of the individuals enrolled in the Atherosclerosis Risk in Communities (ARIC) cohort, a deeply phenotyped population enrolled since the 1980s for a study led by BCM-HGSC researcher Eric Boerwinkle.
By looking for associations between disease phenotypes and loss-of-function mutations, researchers have uncovered nine disease associations in that group, including seven mutations not linked to such conditions in the past.
They have also tracked down far more apparent associations between mutations and potential disease phenotypes that need to be investigated further.
Together, these early adult findings point to the possibility of expanding whole-exome sequencing as a means of not only narrowing in on rare disease culprits, but also for finding new treatment targets and uncovering cases of blended phenotypes and phenotype expansions, Gibbs said.