Participants in a National Institutes of Health-funded study that compared the ability of chromosomal microarrays and karyotyping to detect genetic abnormalities in fetal samples believe that the data set produced is robust enough to convince professional associations like the American College of Medical Genetics to revise their guidelines for prenatal testing in favor of expanded use of arrays.
"I think the study is large enough to influence current guidelines and to inform that process in an important way," David Ledbetter, executive vice president and chief scientific officer for Geisinger Health System, and a co-author on the study, told BioArray News.
"Because of the size of the study and its design, the data should be very useful in updating current thinking and guidelines.," Ledbetter added.
Ledbetter participated in the study while he was director of the Emory Genetics Laboratory, one of five entities to participate in the prenatal study. The other four were New York Presbyterian Hospital-Columbia University Medical Center, Baylor College of Medicine, Signature Genomics, and Genzyme Genetics.
The National Institute of Child Health and Human Development funded the five-year project, entitled "Prenatal diagnosis by array-based copy number analysis." Set to conclude this May, the project has received $5.5 million in funding since its inception in 2007.
Emory, CUMC, Baylor, and Signature used arrays from Agilent Technologies and Affymetrix in the study. Traditional microscope-based karyotyping was performed at Genzyme. After examining more than 4,000 cases over the past five years, 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, leading 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 earlier this month 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 (BAN 2/14/2012). Ledbetter said that the group expects to publish a detailed paper within the next few months.
Chromosomal microarrays are already the primary platform used to detect constitutional abnormalities in postnatal samples. Following an effort by the International Standards for Cytogenomic Arrays Consortium to set rules for array design and data interpretation, ACMG in 2010 updated its guidelines to recommend arrays as the first-tier test for postnatal cases and last year published guidelines for optimal chromosomal array design and data interpretation.
However, the association has not recommended the use of arrays for prenatal samples.
"The current guidelines are to only use chromosomal microarrays as an adjunctive test," said Ledbetter. "They are pretty clear that there is not enough data published to use chromosomal microarrays as a primary test instead of a karyotype," he said.
Despite this, a number of labs have been offering array-based prenatal testing for years. Baylor College of Medicine began testing prenatal samples in 2004 and considers it "regular clinical practice," according to Arthur Beaudet, chair of Baylor's department of molecular and human genetics. Baylor detailed its use of array comparative genomic hybridization to detect abnormalities in more than 1,000 prenatal samples in a 2008 paper in Prenatal Diagnosis.
Beaudet told BioArray News that Baylor's participation in the NIH-funded study has led to more requests for array-based prenatal testing.
"Since the end of the NIH study enrollment, we have seen a significant increase in the number of samples submitted," said Beaudet. "At present we are seeing a rapid increase in the number of samples submitted month by month," he said. "We expect this to accelerate based on the [results presented at the] SMFM meeting."
As a coauthor on the forthcoming paper, Beaudet declined to discuss the study in greater detail. But, like Ledbetter, he said that "everyone in the field expects ACMG and [American Congress of Obstetricians and Gynecologists] to revise their recommendations once the paper is published," though he cautioned that "we will need to wait and see exactly what evolves."
Signature Genomics, part of PerkinElmer, has been offering array-based prenatal testing since 2007. Signature cofounder Lisa Shaffer, now chief scientific officer for molecular diagnostics at PerkinElmer, said that she does not know what ACMG is planning regarding recommendations for prenatal testing. Still, she stressed the significance of the recent study.
"It is the first multi-center trial showing the additional copy number alterations identified after array testing that were missed by karyotyping," said Shaffer, a coauthor on the paper. "Our study demonstrates the superior ability of arrays to detect fetal chromosome anomalies."
Faced with the study's findings, Ledbetter said the medical genetics community would confront a number of scenarios.
"Some proportion of the people in the US and on the European side are mainly focused on pregnancies with abnormal ultrasounds, fetuses with structural abnormalities, for which the published data has already shown a high yield by chromosomal microarray," Ledbetter said. "A limited introduction of chromosome microarray would be only those pregnancies where you have an ultrasound abnormality and a normal karyotype, then the chromosome microarray has the ability to detect a higher frequency of genomic imbalances and current data suggest that this may be cost effective and clinically useful," he said.
The "bigger questions," are whether chromosomal microarray should be offered on pregnancies without structural abnormalities and whether it should be offered only after a normal karyotype or as a first tier prenatal diagnostic test in place of a karyotype. "Either of these latter two options would be much bigger changes in current standards," said
'Very Important Numbers'
Geisinger's Ledbetter also commented on the significance of the findings that arrays could detect additional abnormalities in one out of every 70 fetal samples that had a normal karyotype, and that when a birth defect was detected by ultrasound, arrays found relevant genetic information in 6 percent of cases.
"Those are very important numbers," said Ledbetter. "People want prenatal diagnosis because they are at something like one or half a percent risk of Down syndrome or other major chromosome abnormalities," he said. "And now we are discovering that if you go beyond major chromosomal abnormalities like Down syndrome, there are whole lot of microdeletions and microduplications that are clinically significant and that their cumulative frequency is one out of 70 prenatal samples, six percent when there is an abnormal ultrasound," he noted.
"This is very significant," Shaffer said of the findings. "If 100,000 prenatal cases were tested by array, 6,000 would have abnormal results – stuff that cannot be detected by karyotype analysis," she said.
Noting that 1.7 percent of cases were discovered to have pathogenic copy number variants after a normal karyotype, Shaffer said that if 300,000 of such prenatal tests are performed each year, 5,000 additional cases would be found to have genomic alterations that are clinically significant. These are "very important findings showing arrays are better than karyotyping," she said.
Going forward, Ledbetter said that there is no plan to continue collecting the same kind of data as in the current NIH study. "For the major questions that the NIH study was designed for, the presentation of the data will be such that we think it is meaningful and useful now," he said.
He also said he was "optimistic" that professional associations would move quickly to revisit their existing guidelines given the study's results.
"There is a lot of interest in this particular study's dataset and conclusion," said Ledbetter. He said that the decision of professional associations to weigh whether or not to update current guidelines based on this study "might happen fairly quickly."
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