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Study Finds Array-based Prenatal Testing More Informative than Standard Karyotyping

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By Justin Petrone

Chromosomal microarrays could eventually become the standard of care for prenatal genetic testing in the US if implemented correctly, according to the results of a recent study.

A team of geneticists from New York Presbyterian Hospital-Columbia University Medical Center, Emory University, Baylor College of Medicine, Signature Genomics, and Genzyme Genetics compared chromosomal array-based testing with standard karyotyping to identify abnormalities in fetal samples.

The team used arrays from Agilent Technologies and Affymetrix in the study.

After examining more than 4,000 cases, the team determined that arrays detected additional abnormalities in one out of every 70 fetal samples that had a normal karyotype. When a birth defect was imaged by ultrasound, arrays found relevant genetic information in 6 percent of cases. These findings and others led the team to conclude that arrays were more informative than standard, microscope-based karyotyping to identify genetic abnormalities in prenatal cases.

Principal investigator Ronald Wapner presented data from the study last week at the Society for Maternal-Fetal Medicine meeting in Dallas. In addition, the American Journal of Obstetrics & Gynecology recently published an abstract of the study and is expected to publish a detailed paper within the next few months.

Wapner suggested in a statement that arrays could eventually replace standard karyotyping as the standard of care for screening fetal samples for abnormalities. "Why would anyone want to continue to use the standard method, which gives only part of the answer?" Wapner said.

At the same time, Wapner, who is director of reproductive genetics at New York-Presbyterian Hospital and Columbia University Medical Center, cautioned that it would take time before array-based prenatal testing is fully implemented in reproductive genetic centers in the US.

"We will have to carefully transition this information into clinical practice — to educate physicians and patients, develop guidelines for its use, and learn how to best use it to improve care," Wapner said.

The National Institute of Child Health and Human Development funded the five-year project, set to conclude this May. Called 'Prenatal diagnosis by array-based copy number analysis," it has received $5.5 million in funding since its inception in 2007.

The forthcoming paper is somewhat similar to one that the International Standards for Cytogenomic Arrays Consortium authored in 2009, in which ISCA recommended the use of chromosomal microarrays as a first-tier test for pediatric disorders (BAN 5/18/2009).

Based partially on that statement, the American College of Medical Genetics updated its guidelines in September 2010 to recommend arrays as the first-tier test for constitutional abnormalities in postnatal cases (BAN 9/28/2010). And in July 2011, ACMG laid out guidelines for optimal chromosomal array design and data interpretation (BAN 7/19/2011).

Still, ACMG has not yet moved to recommend array-based testing for prenatal cases. Although US-based labs such as Baylor and Signature have been offering array-based prenatal testing for years, it is performed at the decision of the clinician, and still not considered the standard of care. That makes it more complicated for clients to gain reimbursement for the tests and has slowed adoption of what geneticists like Wapner believe is a higher-resolution way to diagnose abnormalities in fetal samples.

"With karyotyping, we can see only when pieces of the genome of about 5 million base pairs are missing from a chromosome," Wapner said in a statement. "With [chromosomal microarrays], we can see missing pieces of fewer than 100,000 base pairs."

An e-mail sent last week to Wapner seeking comment was not immediately returned. However, in 2010 he discussed the study with BioArray News, calling chromosomal arrays the "next logical step" for prenatal diagnostics. He likened the technology's path to the clinic to the adoption of chorionic villus sampling in the US in the 1980s, claiming that he was among the first to offer CVS in the US.

"What I have done through most of my career is taken the technology that made a lot of sense at its development stage and done the testing to move that technology into clinical care," Wapner said at the time (BAN 6/22/2010). "With [chromosomal arrays], it was decided that the next best step was putting together a clinical trial, putting together lab investigators, understanding how it’s going to be used, and that’s exactly what we are doing," he said of the NICHD-funded project.

Study Design

According to the abstract published in the American Journal of Obstetrics & Gynecology, Wapner's team sought to evaluate the performance of chromosomal microarrays as an independent method for prenatal cytogenetic diagnosis.

To accomplish this, villus or amniotic fluid samples from women undergoing prenatal diagnosis at 31 centers were sent to a central karyotyping lab at Genzyme Genetics. The samples were then split — standard karyotyping was performed on one portion and the other was de-identified and sent to CUMC, Baylor, Signature, or Emory for array-based analysis.

The arrays covered 84 regions of known disease association, 43 centromeric and 41 telomeric regions, and a backbone of oligonucleotides spaced between 75 and 125 kilobases.

Following a preliminary study, most of the analysis was on uncultured samples and culture was used only as a back-up. Karyotype and microarray results were then reported to an independent data center, where microdeletions and duplications identified exclusively by arrays were classified as "of known clinical significance" or "benign" using predefined listings. All other copy number variants were designated as "of uncertain clinical significance."

Altogether 4,401 women were enrolled in the project. Nearly half were of advanced maternal age, a quarter had an abnormal ultrasound, and nearly a fifth had abnormal first or second trimester screenings, with the remaining cases presenting with other indications. Successful results were obtained with arrays in 98.7 percent of cases, and 88 percent were obtained using only uncultured material.

Of the 4,340 samples for which results were available for comparison, karyotyping identified 316 autosomal and 57 sex chromosome non-mosaic aneuploidies. Arrays also identified all of these, but also identified as mosaic seven samples, all obtained from CVS.

The team noted in the abstract that 5.8 percent of cases with a normal karyotype and structural fetal anomalies had either a microdeletion or duplication of potential or known clinical significance, as did 1.7 percent of those sampled for maternal age or positive screening.

The team concluded that for prenatal testing, karyotyping and arrays are "equally effective" in identifying aneuploidy. It added that microarrays detected "additional clinically relevant information both in cases with structural anomalies and in those sampled for routine indications."

"We are looking for the same thing in both tests," Wapner said. "But we find more abnormalities with [arrays]."

Vendors Respond

Companies that provided arrays for the study or offer array-based prenatal testing were quick to promote the team's conclusions this week.

In a statement, Agilent claimed that it was the "primary contributor" of arrays and reagents used in the study. It said that 71 percent of the samples were run on its SurePrint CGH arrays and that its software was used for data analysis. Agilent also said that it assisted the investigators from the prenatal study group in developing the arrays used in the study.

In total, the team used 5,500 arrays in the study, according to Agilent. The Santa Clara, Calif.-based company said that all data will be submitted to the National Center for Biotechnology Information.
CombiMatrix Molecular Diagnostics, which offers array-based prenatal testing on the Agilent platform, also commented on the team's findings this week.

Judd Jessup, president and CEO of CombiMatrix, said in a statement that the study "demonstrates conclusively" that array-based prenatal testing can allow expectant parents to "better understand the potential impacts of genetics on their child than the standard karyotyping test that has been used for decades."

In the June 2010 interview, Wapner said that the Agilent and Affy chips were selected to serve the team's greater objectives.

"Our job was not to compare the two arrays," Wapner said at the time. "It was to ask the question of what is the value of arrays in clinical practice."


Have topics you'd like to see covered inBioArray News? Contact the editor at jpetrone [at] genomeweb [.]com

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