It's a "critical time" for array-based prenatal diagnostics, according to Lisa Shaffer, chief scientific officer of molecular diagnostics at PerkinElmer and cofounder of its Signature Genomics business.
With the results of a National Institute of Child Health and Human Development-funded project that found array-based prenatal testing to be more informative than conventional karyotyping expected to appear soon, Shaffer told BioArray News that professional organizations will be "scrutinizing the prenatal use of microarrays and likely releasing position statements" (BAN 2/14/2012), BAN 2/21/2012).
To better inform those who will be evaluating array-based prenatal tests for clinical use, Shaffer and her colleagues at Spokane, Wash.-based Signature recently published two papers in the journal Prenatal Diagnosis.
"We knew we had sizable experience with prenatal microarrays and wanted our data to be part of the published literature to be available to these groups," Shaffer said. She added that while Signature did take part in the NICHD-funded study, none of the cases discussed in the papers was part of the NICHD study.
The first paper details Signature's experience with microarray-based comparative genomic hybridization for prenatal diagnosis in more than 5,000 pregnancies since it began offering testing as a service in 2004.
According to the paper, the overall detection rate of clinically significant copy number alterations among unbiased, nondemise cases was 5.3 percent, while detection rates were 6.5 percent and 8.2 percent for cases referred with abnormal ultrasounds and fetal demise, respectively.
In addition, the overall rate of findings with unclear clinical significance was 4.2 percent but this would fall to 0.39 percent if only de novo CNAs were considered, Shaffer and colleagues wrote.
In cases with known chromosomal rearrangements in the fetus or parent, 41.1 percent showed CNAs related to the rearrangements, while 1.3 percent showed clinically significant CNAs unrelated to the karyotype. Finally, Signature reported that 71 percent of the clinically significant CNAs found by microarray were below the resolution of conventional karyotyping of fetal chromosomes.
The second paper focused specifically on the detection rates of clinically significant genomic alterations by microarray analysis for specific anomalies detected by ultrasound.
Shaffer and colleagues performed a retrospective analysis of 2,858 pregnancies with abnormal ultrasounds and normal karyotypes, when karyotypes were performed, that were tested using CGH microarrays. They stratfied abnormalities according to organ system involvement and calculated the detection rates for clinically significant findings among these categories.
According to the paper, microarray analysis identified clinically significant genomic alterations in 6.5 percent of cases with one or more abnormal ultrasound findings, and the majority were below the resolution of karyotyping.
Based on the results of both analyses, Shaffer and coauthors argued that microarray analysis "has advantages over conventional cytogenetics," including the "ability to more precisely characterize CNAs associated with abnormal karyotypes." Moreover, they wrote in the second paper that a "significant proportion of cases studied by array will show a clinically significant CNA even with apparently normal karyotypes."
Of the team's findings, Shaffer said that "it is important to keep in mind that, for the most part, these rates represent detection of clinically significant abnormalities above and beyond what traditional karyotyping can show."
In the case of abnormal ultrasounds, Shaffer said that Signature showed that microarrays offer an approximately 50 percent increase in detection rates over karyotype.
She added that there are other benefits beyond detection rates. In the case of fetal demise, Shaffer said that cells frequently do not grow well in culture, which prevents the ability to karyotype, while microarray experiments do not require culturing to get results.
And in the case of abnormal karyotypes, the karyotype alone may have some ambiguity, Shaffer said. "For example, a marker chromosome is seen, but the material that makes up the marker is not known." Array results in conjunction with karyotype results in these cases can provide additional clarity, according to Shaffer.
"An array can identify the makeup of a marker chromosome, or, if it does not identify any additional genetic material, this means the marker is likely lacking in gene-rich euchromatin that poses a risk for the development of an abnormal phenotype," she said.
Signature has used a variety of arrays over the years, ranging from internally made bacterial artificial chromsome arrays to higher-resolution oligonucleotide arrays.
For the two studies, Signature chose to combine data from multiple platforms so that it could have "larger denominations," Shaffer said. That being said, the majority of the cases were run on oligonucleotide-based arrays with whole-genome coverage.
Despite the new papers, and many others like them, Shaffer said that conventional karyotype is still the only test performed following invasive diagnostic procedures, especially in low-risk populations.
"There are variable reasons for this, including fear of unclear results and sometimes financial reasons or lack of insurance coverage for the testing," she said.
"This tells us that there is no consensus on how microarrays should be used prenatally and in what populations," Shaffer added. "Therefore, we published our data to further demonstrate what arrays can do in various populations of pregnant women to try to provide more information to make such decisions."