GeneDx has launched a prenatal Noonan syndrome spectrum test that runs on Illumina's MiSeq, taking advantage of the platform's short turnaround time, and is planning additional prenatal next-gen sequencing panels. Also, the company recently released an expanded version of its diagnostic whole-exome sequencing test that includes the mitochondrial genome and plans to offer a focused version of the test that only analyzes a small subset of the genes.
The Gaithersburg, Md.-based firm has been offering testing for Noonan syndrome spectrum disorders — which include several related conditions with symptoms such as short stature, cardiovascular defects, developmental delays, and characteristic facial features — since 2002, first postnatally and later also prenatally.
Testing started with capillary sequencing of a single gene and expanded over time to eight genes that were analyzed sequentially in five tiers, which could take up to 20 weeks. The lab then transitioned to Affymetrix resequencing arrays, which reduced the turnaround time to two to three weeks but still required several amplicons that were not covered well to be sequenced by Sanger. The array technology allowed the lab to offer the test both pre- and postnatally, but the data analysis could take up to four hours, and the technology was difficult to test and validate, according to Sherri Bale, GeneDx's managing director.
GeneDx then switched over to the Illumina HiSeq 2000 for postnatal testing, a test that includes 11 genes, of which three amplicons still need to be sequenced by Sanger technology. But the speed and the logistics of the HiSeq, which requires many samples to be batched to be cost-effective, meant that the turnaround time was not fast enough for prenatal testing. "For prenatal samples, we needed more flexibility. We wanted to run smaller batches with faster turnaround times," said Yuriy Shevchenko, the company's chief technology officer. "It was not until the arrival of the MiSeq that we could design this panel using the TruSeq [method], and implement it in what we call our FastGen lab."
The new prenatal MiSeq test, which GeneDx started offering several months ago at a price of $2,500, uses a TruSeq Custom Amplicon library to amplify eight genes associated with Noonan spectrum disorders, a total of 147 exons or 21 kilobases of DNA. Two amplicons are sequenced by Sanger technology because they are not covered sufficiently by next-gen data, and up to 16 samples can be analyzed in a single MiSeq run. The test also requires less input DNA than the resequencing array-based test – about 250 nanograms instead of several micrograms.
The lab promises a turnaround time of three weeks at the moment, but the actual turnaround time is more like 7 to 8 days, which could be further reduced if more samples come in and the MiSeq could run more often. In addition, GeneDx is about to finish validation of a protocol to sequence DNA from cells from amniotic fluid or chorionic villus directly without culturing, which could shave another three days or so off the turnaround time.
The lab runs about 15 of the new prenatal Noonan tests per week on average and as of last month had analyzed about 120 samples. The test is ordered when a first-trimester ultrasound screen shows increased nuchal translucency. Doctors have so far mostly ordered karyotyping and array-CGH tests first, but according to Swaroop Aradhya, director of GeneDx's neurogenetics program, the evidence for ordering the Noonan test first is growing because it has a higher positive rate for picking up Noonan syndrome.
GeneDx, which is owned by Bio-Reference Laboratories, plans to launch other prenatal panels in the future, including a test for skeletal dysplasia that it hopes to start offering later this year. According to Aradhya, no comprehensive tests are currently available for distinguishing between different types of skeletal dysplasia, and a large number of genes are involved, making it "a good disorder group for us to think about doing prenatal testing."
In addition to developing prenatal next-gen sequencing tests, GeneDx has been expanding its HiSeq-based XomeDx whole-exome sequencing test for diagnosing difficult genetic disorders (CSN 10/19/2011). The test, which the company launched about a year ago, is "without a doubt our fastest-growing test," Bale said, adding that the firm has been adding personnel to accommodate demand. "The uptake has been tremendous."
The company recently added the mitochondrial genome, sequenced on the MiSeq, calling the new version XomeDx Plus. In addition, it has been working on speeding up the test, which according to its website has a turnaround time of 12 to 14 weeks. Bale said the bottleneck for the test is still the interpretation, which is "not as automatable as we might like it to be" and requires individuals with clinical and molecular expertise.
Within a month or so, GeneDx also plans to launch a focused version of the test, called XomeDx Slice, that will sequence the entire exome but only analyze subsets of genes known to be associated with a specific phenotype, according to customers' orders. This targeted analysis will shorten turnaround time by at least four weeks and price by two-thirds to three-quarters, Bale said. It will also not require parents to be sequenced. "We are hoping that the more academic-minded clinicians would use this," she said.