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Genome Sequencing Provides Diagnostic Boost for Intellectual Disability, but Cost Remains Higher

NEW YORK – An international team led by investigators in Australia has demonstrated that whole-genome sequencing can achieve a higher rate of diagnoses than conventional exome sequencing in a cohort of individuals with intellectual disability, though the price tag remains considerably higher.

"Despite significant molecular diagnostic improvements, approximately half of the individuals with [intellectual disability] remain undiagnosed after exome sequencing," senior and corresponding author Tony Roscioli, a researcher with Neuroscience Research Australia, the University of New South Wales, and Prince of Wales Hospital, and his colleagues wrote in Genetics in Medicine on Friday, noting that genome sequencing "increases coding region coverage consistency, has improved detection sensitivity for structural variants … and facilitates the detection of noncoding and mitochondrial variation."

For their analyses, the researchers considered exome sequences, short-read genome sequences, EpiSign DNA methylation test-based epigenetic signatures, and long-read sequences for 74 individuals with intellectual disability aged 6 to 43 years, along with their parents.

In these trios, the exome sequencing strategy led to pathogenic or likely pathogenic variants in 42 of the cases, or 57 percent of those profiled, while genome sequencing data made it possible to diagnose another nine cases that would have remained unsolved after the trio exome sequencing step.

In the process, the investigators highlighted a dozen candidate genes for intellectual disability, including NR2F1, MED13L, YARS1, and SCN2A.

All but one of the genetic culprits in cases diagnosed by genome sequencing were subsequently picked up by applying a more up-to-date exome sequencing pipeline, the researchers noted, adding that epigenetic signatures provided clues in a small but significant subset of diagnoses.

Even so, the team's health economic analysis suggested that the cost of making diagnoses with a first-line genome sequencing approach was far higher than that associated with exome sequencing followed by genome sequencing in exome-negative cases. The former strategy carried an estimated cost of $7,062 for each diagnosis made, compared to $4,986 per diagnosis using updated exome sequencing followed by genome sequencing in cases that remained undiagnosed.

Based on their results, the investigators estimated that first-line genome sequencing-based diagnoses in intellectual disability would be comparable in price to exome sequencing-based diagnoses if the price of genome sequencing came down by roughly 61 percent, to just over $2,400 per parent-child trio.

Using their original exome sequencing pipeline, the researchers estimated that the average cost per exome-based diagnosis came in at $3,261, though the price dipped to $2,739 per diagnosis on average with updated exome sequencing.

They put the average cost per diagnosis at $5,740 when using the original exome sequencing pipeline followed by reflex genome sequencing, compared to $4,976 when genome sequencing was used after the newer exome sequencing pipeline.

"This study demonstrates that first-line [genome sequencing] achieves a higher diagnostic rate than contemporary [exome sequencing], but at a higher cost," the authors concluded.