NEW YORK (GenomeWeb) – Researchers at Children's Mercy in Kansas City have assessed the clinical utility and cost-effectiveness of exome and genome sequencing for diagnosis in a retrospective study of 119 children with neurodevelopmental disorders.
Based on their results, they suggested that trio exome and genome sequencing should be used early in the diagnostic process, rather than as a last resort, and that fast genome sequencing should be used in urgent cases.
As a follow-up to their study, the researchers are planning to launch a prospective randomized clinical trial to test the effectiveness of whole-genome sequencing compared to the standard of care.
For their study, which was published online in Science Translational Medicine today, the team, led by Stephen Kingsmore and Sarah Soden at the Center for Pediatric Genomic Medicine at Children's Mercy, analyzed 119 children with neurodevelopmental disorders from 100 families who had undergone exome or genome sequencing at the center, some of them rapid whole-genome sequencing. Overall, the diagnostic yield was 45 percent, and half of those who received a diagnosis saw either a change in their management or in the "clinical impression" of their disease.
"It was somewhat surprising that we had such a strong diagnostic rate," given the low amount of consanguinity in the families, said Soden, the study's lead author and a developmental pediatrician. "But what was much more surprising for me was that we were able to influence patient care as often as we did."
The study focused on the first 100 families affected by neurodevelopmental problems that were enrolled in Children's Mercy's research program to diagnose pediatric monogenic disorders by whole-genome and whole-exome sequencing over a period of almost three years. In most cases, parent-child trios were tested.
Eighty-five families, whose children were seven years old on average, received exome sequencing on either the Illumina HiSeq 2000 or 2500. For six patients where the exome yielded no diagnosis, this was followed by whole-genome sequencing on the Illumina HiSeq X Ten.
Fifteen families, whose children showed symptoms at or shortly after birth and were treated in intensive care units, received rapid whole-genome sequencing on the HiSeq 2500, an assay called STAT-Seq that was developed by Children's Mercy in collaboration with Illumina. The assay takes about 50 hours to perform, and the fastest time to a confirmed diagnosis for one of the patients was six days. Time to diagnosis was longer in cases where the genetic disease was only recently described or entirely new, or in patients whose phenotype was atypical for the disease.
Forty-five percent of families and patients received a definite molecular diagnosis based on the test, and candidate genes were identified in another nine families. About half the pathogenic variants were dominant de novo mutations.
The diagnostic yield differed between the critically ill infants and the chronically ill older children: 73 percent of families who underwent rapid whole-genome sequencing received a diagnosis, but only 40 percent of the other families did, including one of the six who received whole-genome sequencing after a negative exome test.
A diagnosis changed the patient's management or the "clinical impression of the pathophysiology," which Soden said means a "shift in thinking about the patient" that often changes his or her care, in almost half of the 45 families. For 10 children, the diagnosis led to new therapy with drugs or dietary treatments, to which two of them responded favorably. In three cases, patients discontinued unnecessary treatments, and nine diagnoses led to evaluations for possible complications of the disease.
To gauge the cost-effectiveness of exome and genome sequencing, the researchers tallied the total cost of diagnostic testing that families had previously incurred. Rather than comparing those costs to their internal research costs for exome and genome sequencing, which Soden said would have been an unfair comparison, they calculated how much exome or genome testing could cost at most to be cost-competitive with the sum of the other diagnostic tests.
Families with older children who received a diagnosis had been charged a mean of $19,100 for prior diagnostic testing, ranging from about $3,000 to $55,000. Given the 40 percent diagnostic yield of exome and genome sequencing in that group, the researchers estimated that it would be cost-effective at $7,640 per family, which Soden said is on the order of what clinical laboratories currently charge for trio exome testing.
For the 11 families who received rapid whole-genome sequencing, the mean charge for conventional diagnostic testing was $9,550, ranging from less than $4,000 to more than $14,000, but the researchers did not calculate the cost at which genome sequencing would be competitive in that group. Soden noted that the internal cost of the rapid STAT-seq test is many times the cost of conventional whole-genome sequencing.
More research will be needed to get a more definite answer about the clinical- and cost-effectiveness of genome and exome sequencing. "While this is a very rich dataset, it's limited by being retrospective," Soden said. "The natural next step is a prospective study."
One such study, funded by the National Institute of Child Health and Human Development and the National Human Genome Research Institute, uses the STAT-Seq test and is already ongoing at Children's Mercy to compare whole-genome sequencing in sick and healthy newborns to standard newborn screening and diagnostic testing.
Another prospective randomized trial will be launched as soon as it is approved, Soden said. That study will include approximately 100 families affected by neurodevelopmental disorders that present to specialty clinics for evaluation. Part of that group will receive whole-genome sequencing at the beginning of the study, while the others will have their genomes sequenced after a year, and all patients will obtain the standard of care.
The study is currently funded with $250,000 from the A.P. Giannini Foundation and will seek additional funding to expand and to follow families over time.
Diagnostic microarrays are still being used as part of this and other studies, Soden said. "Microarray findings are still critically important for our patient population," she said, though they might be replaced by sequencing in the long run.
Based on their published study, the authors concluded that sequencing of genomes or exomes of trios "should become an early part of the diagnostic work-up of [neurodevelopmental disorders]" and that rapid sequencing should be "extended to patients with high-acuity illness."
Unlike other medical centers and some commercial laboratories, Children's Mercy currently does not offer either exome or genome sequencing as a clinical diagnostic test, instead providing a targeted gene panel for childhood diseases called TaGSCAN.
"We are deciding what we are going to do," Soden said. "Remaining in the research world a little bit longer allows us the opportunity to explore, so that when we decide what we want to do next, it's based on a lot of good information."