NEW YORK (GenomeWeb) – Rapid whole-genome sequencing has already been used to diagnose critically ill infants with suspected genetic diseases within days, but the cost of the approach remains high. As a potential alternative, GeneDx recently implemented a rapid exome sequencing test called XomeDxXpress in its diagnostic laboratory.
At the American College of Medical Genetics and Genomics annual meeting in Tampa last week, Jane Juusola, director of GeneDx's whole exome sequencing program, presented results for the first 100 cases.
The analysis suggests that the test, which delivered initial results within five days on average, has considerable clinical utility: 47 percent of patients received a definite molecular diagnosis, which in many cases led to a change in medical care or management, averted additional diagnostic tests, and facilitated family planning. GeneDx is now working with providers to study the impact of the test, which is priced about 50 percent higher than its standard exome test, on overall healthcare costs.
The test, which analyzes the exomes of patient-parent trios and requires clinical information, is intended for patients who may benefit from a rapid genetic diagnosis, in particular pediatric patients in the intensive care unit.
"In the case of a young child in the NICU or PICU, the physicians and families are looking for answers and need to make timely decisions for very sick children," Juusola told GenomeWeb. "The faster they are able to get a diagnosis or rule something out, the sooner they can implement treatment decisions which can lead to the child no longer being in an expensive critical care unit."
Rapid exome sequencing requires close coordination with the ordering physician, she said, so when the samples arrives, they can be sequenced and analyzed as quickly as possible.
The actual test is the same as the standard exome sequencing test GeneDx offers but rapid exome samples are prioritized for every step of the workflow, she said.
Following a clinical review of the exome data, definite diagnostic results as well as secondary findings in the 56 ACMG-recommended genes are reported to physicians verbally within five to seven days. This is followed by Sanger confirmation of reportable variants and further medical review, and a final report is issued within 14 to 16 days.
So far, GeneDx has completed about 150 rapid exome cases and Juusola reported results for the first 100 last week.
Patients' ages ranged from two days to 17 years, but the overwhelming majority were younger than two years, and half the patients were younger than one year. Twenty-nine patients came from consanguineous families.
For about half of patients, the primary clinical indication was multiple congenital anomalies. Others included cardiovascular, immunologic, neurologic, and hematologic problems.
Many families sought a rapid diagnostic result because the patient was acutely ill and was treated in the neonatal or pediatric intensive care unit. Others were international patients who were only in the US for a limited time and wanted to receive results before they went home. A number of families had both an affected child and an ongoing pregnancy and wanted to get a quick diagnosis to be able to make decisions about the pregnancy. Others needed to decide on stem cell or organ transplants, where a genetic diagnosis would be helpful.
For 47 percent of patients, the rapid exome provided a definite diagnosis, based on pathogenic variants known to be associated with their phenotype. In another 25 percent, the test came up with variants of unknown significance in genes that may be associated with their phenotype, and for 8 percent, the test detected variants in candidate genes that had not been previously associated with disease. For 20 percent of patients, no variants possibly associated with their phenotype were detected.
Of the definite diagnoses, 24 were for autosomal recessive disorders, 20 for de novo autosomal dominant diseases, three for inherited autosomal dominant diseases, and three for X-linked disorders. Three of the patients received two separate molecular diagnoses, and no patient had a secondary finding.
At almost 50 percent, the rapid exome test had a much higher diagnostic rate than the standard exome test, which has provided a diagnosis in about 30 percent of cases tested at GeneDx. According to Juusola, there are a few reasons for this: For a start, the rapid exome was used as a first-line test, whereas patients receiving the regular exome test often had significant previous diagnostic workup. However, she said that the lab did not find many "low hanging fruits" in the rapid exomes, meaning mutations that could have been detected by a single-gene test or a gene panel.
The family trio approach likely also boosted the diagnostic rate compared to the standard exome, which sometimes only analyzes the patient's DNA.
The turnaround time of the rapid exome test ranged from three days to 10 days for the initial verbal results, with an average of five days, whereas the written report was issued within four to 18 days, with an average of 10 days.
Longer times were sometimes related to technical issues. One report was late, for example, because the bioinformatics pipeline was updated over the weekend, Juusola said, and in another case, a sample failed and needed to be resequenced. Also, it sometimes took a while to confirm copy number variants for the final report.
The results affected patients and their families in various ways. Of 58 patients for whom GeneDx has follow-up data available, 22 had a change in their medical care, 25 avoided additional diagnostic tests, and for 12, palliative care was discussed. In 28 cases, the results facilitated carrier testing and planning of future pregnancies.
To illustrate the clinical utility of the test, Juusola presented two patient cases. In one newborn patient, the test discovered a homozygous mutation in the BRAT1 gene, which led to a diagnosis of lethal neonatal rigidity multifocal seizure syndrome. This resulted in the cancellation of a scheduled muscle biopsy and allowed the baby to leave the hospital early and start hospice care at home. The family also received genetic counseling on the recurrence risk and can opt for prenatal testing in the future.
In the second case, a pediatric patient received a dual diagnosis of Wiedemann-Steiner syndrome and Niemann-Pick C syndrome, based on compound heterozygous mutations in the NPC1 gene and a de novo mutation in the KMT2A gene. As a result, the family was able to consider treatment with a drug that has been approved for treatment of NPC in a number of countries and enrollment in a clinical trial for another drug. It also received genetic counseling for family planning and was able to have an older brother tested for the disease, which sometimes only shows symptoms at a later age.
Going forward, studies will be needed to prove that the rapid exome test not only has clinical utility but is also cost effective. Juusola told GenomeWeb that the test has saved money in several cases by avoiding invasive procedures and allowing patients to leave intensive care units sooner than they would have otherwise.
"We are now working with our clinicians to gather detailed data to substantiate our observations," she said, adding that the company is interested in working with providers on prospective and retrospective studies of how rapid exome testing impacts overall healthcare costs.
At the moment, she said, the test is covered as part of a patient's care in the intensive care unit and is covered under so-called Diagnosis-Related Group (DRG) codes instead of being billed to insurance as a separate item.
GeneDx is one of several places that have implemented rapid diagnostic genetic testing. Researchers at Children's Mercy Hospital in Kansas City pioneered fast genome sequencing in 2012, with a test called STAT-Seq, but the cost of that test, which can have turnaround times of as little as 26 hours, remains high, with a recent estimate of about $8,000 per sample. Also, Baylor College of Medicine reported last year that its diagnostic laboratory has implemented a "lightning exome" test, with a turnaround time of less than three days.