NEW YORK (GenomeWeb News) – Microarrays can provide more clinically relevant information than traditional karyotyping, and should become the standard approach in prenatal diagnostics going forward, according to a paper appearing today in The New England Journal of Medicine from researchers at Columbia University Medical Center and elsewhere.
An editorial discussing the paper and its ramifications also appeared in the same journal, as did two other papers assessing genomic methods for prenatal diagnosis — one that studied the use of arrays to detect abnormalities in stillbirths and another that used sequencing for the clinical diagnosis of a prenatal sample.
The authors of the Columbia-led paper aimed to compare the amount of clinically relevant information that could be obtained from arrays versus karyotyping, which has been the standard of care since the 1970s.
Using arrays manufactured by Affymetrix and Agilent Technologies as well as karyotyping, the researchers conducted a blinded trial of 4,400 patients at 29 centers across the US over a four-year period. Amniotic fluid samples were collected from women with advanced maternal age and those whose fetuses were shown in early screening to be at heightened risk for Down syndrome, to have structural abnormalities as seen with ultrasound, or to have indications of other problems.
Lead author Ronald Wapner, professor and vice chairman for research of the department of obstetrics and gynecology at CUMC, was the principal investigator on the study.
According to the paper, the investigators found that array-based analysis performed as well as karyotyping in identifying common aneuploidies, instances of having abnormal number of chromosomes, which in turn can cause genetic disorders such as Down syndrome and Edwards syndrome. Moreover, among fetuses in which a growth or structural anomaly had already been detected with ultrasound, microarrays were able to detect clinically relevant chromosomal deletions or duplications in 6 percent of cases, changes that were not observed with karyotyping the same samples. Additionally, in cases sampled for advanced maternal age or positive screening results, array analysis picked up an abnormality in one out of every 60 pregnancies, about 1.7 percent of all cases, that had a normal karyotype.
Based on these results, Wapner said in a statement this week that arrays "will and should replace karyotyping as the standard for evaluating chromosomal abnormalities in fetuses," adding that chromosomal microdeletions and duplications found with microarray are "often associated with significant clinical problems."
Currently, samples used in array analyses require fetal cells obtained via invasive procedures, such as amniocentesis, or chorionic villus sampling. Should a noninvasive means for testing fetuses for genetic abnormalities become available, Wapner said that all women, not just those in special risk categories, should have access to the information obtainable by array analysis.
"We hope that in the future — when microarray can be done non-invasively — every woman who wishes will be offered microarray, so that she can have as complete information as possible about her pregnancy," Wapner said in a statement.
Wapner and colleagues noted in the paper that "lessons learned from microarray analysis will be helpful when whole-genome sequencing of the fetus, perhaps with the use of maternal blood samples, becomes clinically available and should help to ensure the sensible application of new technology."
Such sequencing-based tests are already being commercialized by several firms, such as Sequenom, Ariosa Diagnostics, and Verinata Health, for non-invasive prenatal diagnosis of aneuploidy.
Wapner did not respond to questions about the study in time for this publication. However, GenomeWeb Daily News sister publication BioArray News spoke with Wapner at length about the study two years ago (BAN 6/22/2012), and about a National Institutes of Health-funded follow-on study that commenced earlier this year (BAN 4/3/2012).
For the new project, researchers led by Wapner will use a five-year, $5 million grant from the National Institute of Child Health and Human Development to track pediatric patients who had an abnormal array result of unclear significance over a three-year period to obtain phenotypic information that may result from the abnormality. The team also intends to build an interactive online educational resource for test providers and patients.
"Unfortunately, it is sometimes difficult to predict the full spectrum of some diseases indicated by a particular deletion or duplication," Wapner said. "We are studying what these mean clinically, and science continues to catch up with our ability to obtain the information."
Wapner first presented data from the prenatal study earlier this year at the Society for Maternal-Fetal Medicine meeting in Dallas. Since then, several study participants have said they believed the study could influence decision makers to revisit guidelines concerning prenatal genetic testing.
"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 in April. "Because of the size of the study and its design, the data should be very useful in updating current thinking and guidelines," Ledbetter added.
The American College of Medical Genetics and Genomics updated its guidelines two years ago to recommend microarrays as a first-tier diagnostic test for the postnatal evaluation of patients with developmental delay or intellectual disability, autism spectrum disorders, or multiple congenital anomalies.
However, the organization's guidelines continue to state that arrays should only be used as an adjunctive test to karyotyping in a prenatal setting. Despite this, many institutions and companies have been offering array-based prenatal testing for years.
Baylor College of Medicine was arguably first in the US to begin offering array-based prenatal testing in 2004, and others, such as Signature Genomic Laboratories (now part of PerkinElmer) and CombiMatrix Molecular Diagnostics began offering similar services in following years. In these services, the arrays, which are marketed for research use only, are included in assays performed as laboratory-developed tests in Clinical Laboratory Improvement Amendment-compliant facilities, and the findings are confirmed using other technologies, such as fluorescence in situ hybridization.