Chromosomal microarray testing is equivalent to standard karyotype testing for prenatal diagnosis of common aneuploidies, and it provides additional clinically relevant information that karyotyping cannot, according to a report published online Dec. 6 in the New England Journal of Medicine.
In a study comparing the yields between these two techniques for routine detection of fetal disorders among more than 4,000 pregnant women, microarray testing identified important genetic anomalies missed by karyotyping in 1.7% of pregnancies with the usual indications for diagnostic testing (such as advanced maternal age) and 6% of cases in which ultrasound had revealed an anomaly.
"These data indicate a benefit to chromosomal microarray analysis as a standard part of prenatal testing, bearing in mind that, as with karyotyping, the detection of variants of uncertain clinical significance presents a challenge for counseling and cause [patients] anxiety," said Dr. Ronald J. Wapner of Columbia University Medical Center, New York, and his associates.
In fact, if microarray testing proves to have a similar yield of positive results in confirmation studies, "offering invasive testing and microarray analysis to all pregnant women would seem to be appropriate. This is consistent with the recommendations of the American Congress of Obstetricians and Gynecologists, who suggest that all women, regardless of their risk, should be offered the option of invasive testing," they noted.
Until now, microarray testing has been assessed as a method for prenatal diagnosis only in small studies of pregnancies with a high likelihood of chromosomal abnormalities, such as those in which the fetus is known to have structural anomalies. But it was not known whether the technique would reliably detect all the chromosomal abnormalities that are identified by standard karyotyping, let alone whether it would detect additional chromosomal abnormalities.
"We conducted a large, prospective study of prenatal diagnostic samples to assess, in blinded fashion, the ability of microarray analysis to diagnose common chromosome abnormalities and to gauge the extent of additional information provided by microarray analysis as compared with standard karyotyping," Dr. Wapner and his associates wrote.
They screened 6,537 women with singleton pregnancies who presented to 29 prenatal diagnostic centers for either chorionic villus sampling (CVS) or amniocentesis in 2008-2011. They then enrolled 4,406 of these women who had indications such as advanced maternal age, a positive result on aneuploidy screening, or fetal structural anomalies detected on ultrasound, and who had adequate samples from CVS (2,275 pregnancies) or amniocentesis (2,131 pregnancies).
Microarray testing was successful in 4,340 (98.8%) of these cases. Fifty-eight of these were then excluded because the samples showed mosaicism on karyotyping.
Standard karyotyping identified common autosomal aneuploidies in 7.4% of the remaining 4,282 samples and sex-chromosome aneuploidies in another 1.3%. Microarray testing also identified all of these aneuploidies. Moreover, the microarray method indicated that another eight of the CVS samples showed probable mosaicism.
More important, microarray analysis identified clinically significant segmental aneuploidies that had not been detected on karyotyping. Overall, 2% of the samples that showed normal karyotypes were found to have clinically significant copy-number variants on microarray testing, the investigators said (N. Engl. J. Med. 2012;367:2175-84).
In the subgroup of 755 samples from pregnancies with suspected growth or structural anomalies, 6% showed clinically relevant findings on microarray that were not detected on karyotyping.
Similarly, in the subgroup of 1,966 pregnancies that didn’t show anomalies on ultrasound but were referred for prenatal testing because of advanced maternal age, microarray analysis detected chromosomal abnormalities in 1.7% that were not detected on karyotyping.
Microarray testing also flagged 130 cases that were normal on karyotyping but showed chromosomal abnormalities "of uncertain significance." In 36 of these, the findings were judged to be "probably benign"; the remaining 94 cases were referred to an expert committee so their clinical relevance could be adjudicated. The committee judged 61 of these cases to be concerning enough that the patient should be informed of the chromosomal abnormality.
However, during the interval since the inception of this study 5 years ago, researchers have made considerable progress in determining whether most of these "uncertain" findings are either benign or clinically significant. If the currently available data had been used to adjudicate these 94 samples, only 56 would have been judged as "of uncertain significance," while 30 would have been categorized as clearly pathogenic and 8 as probably benign.
"With this additional information, the pathogenicity of only 1.5% of copy-number variants detected on microarray in karyotypically normal samples remains ‘uncertain,’ and this number should continue to fall as additional experience is acquired," Dr. Wapner and his associates said.