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Genetic Testing Evaluated For Diagnosing Epilepsy, Monogenic Conditions

NEW YORK (GenomeWeb) – Two new independent studies suggest that microarrays, exome sequencing, and other broad genetic profiling methods can narrow in on mutational culprits in a significant proportion of pediatric epilepsy cases or cases involving children with undiagnosed monogenic conditions.

For one of the JAMA Pediatrics studies, published today, researchers from the Ann & Robert Lurie Children's Hospital of Chicago, Northwestern University, and elsewhere recruited 775 families with children diagnosed with epilepsy before the age of three. Nearly half of the 680 affected children without acquired brain injuries — 327 of the cases — received some form of genetic testing for the study.

The team found pathogenic variants in more than 40 percent of the children who received genetic testing, including about 44 percent of those profiled by karyotyping, 17 percent of pediatric epilepsy cases assessed by microarray, more than 27 percent of children tested with epilepsy sequencing panels, and 20 percent of mitochondrial panel-tested children.

The team reached diagnoses for eleven of the 33 epilepsy-affected children tested by whole-exome sequencing and nearly 30 percent of the 94 cases assessed using other genetic testing approaches.

"We found that genetic sequencing tests have a very high diagnostic yield, much more than some of the other tests that are routinely performed in initial work-up of early life epilepsy," first author Anne Berg, a pediatric neurology researcher affiliated with the Ann & Robert H. Lurie Hospital of Chicago and Northwestern University, said in a statement. "Arriving at an accurate genetic diagnosis also would make many other tests unnecessary."

And in a subset of 180 children who had unexplained etiology when the study began, such approaches — particularly the exome sequencing and epilepsy sequencing panels — led to diagnoses almost one-third of the time, compared with a diagnostic yield of 8 percent with chromosomal arrays in that group of children.

The ability to make such diagnoses is a critical component in realizing the promise of precision medicine, according to Berg, who argued that genetic testing "should be incorporated into the routine initial evaluation of young children with epilepsy."

In the second study, an independent team led by investigators in Australia focused on genetic diagnoses made by whole-exome sequencing in children with mysterious conditions believed to stem from mutations in a single gene. As part of a Melbourne Genomics Health Alliance demonstration project, the researchers analyzed the diagnostic rates and the cost-effectiveness associated with whole-exome sequencing done at various points in a patient's diagnostic journey.

They found that more than half of the 44 children tested by singleton exome sequencing received a diagnosis, including eight cases where diagnoses were not anticipated. On average, each of the children included in the study had already gone through 19 tests over some six years, they noted, and more than half had undergone procedures that required general anesthetic in an attempt to reach diagnoses.

When the team took the cost of such tests into account, it estimated that it would be possible to save between almost $3,300 and $11,700 per additional diagnosis by using whole-exome sequencing as an early-stage diagnostic tool, during initial tertiary presentation rather than a standard diagnostic pathway.

"Even if [whole-exome sequencing were performed at the first genetics appointment," the authors wrote, "there would be an incremental cost savings of A$5,461 (US$4,140) … per additional diagnosis compared with the standard diagnostic pathway."

In an accompanying editorial in JAMA Pediatrics, University of Leipzig human genetics researcher Johannes Lemke noted that the ability to reach a diagnosis in such situations "may not only be of prognostic value, but also put an end to a possibly stressful and demanding diagnostic odyssey."

Touching on results reported by both teams, Lemke wrote that such studies support the notion that high-throughput sequencing may uncover mutation culprits missed with chromosomal array-based approaches, making it a candidate for first-tier diagnoses in individuals with congenital diseases and other early-onset conditions.