Microarray for Prenatal Diagnosis

Abstract & Commentary

By John C. Hobbins, MD, Professor of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, is Associate Editor for OB/GYN Clinical Alert.

Dr. Hobbins reports no financial relationships relevant to this field of study.

Synopsis: In diagnostic amniocentesis and chorionic villus sampling, microarray detects a wider breadth of clinically meaningful chromosomal abnormalities than standard karyotype.

Source: Wapner RJ, et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med 2012; 367:2175-2184.

It has only been a few months since maternal cell free DNA (cfDNA) testing for trisomies 21, 18, and 13 burst onto the scene to shake up (in a good way) current prenatal testing protocols.1 Now, in the December issue of the New England Journal of Medicine, a report has emerged that will further change the entire face of prenatal diagnosis.2

Microarray technology is based on the ability to detect small micro-deletions and duplications by pinpointing abnormal variations in the number of copies of particular DNA segments (copy number variants). Although microarrays have been used diagnostically in other clinical arenas such as stillbirth and pediatric neurological conditions (e.g., some forms of the autism spectrum), the study by Wapner et al is the first to apply this methodology to prenatal diagnosis.

The study enrolled 4406 women in 29 centers who had had an amniocentesis or chorionic villus sampling (CVS) for advanced maternal age (46.6%), abnormal aneuploidy screening (18.8%), or an abnormal ultrasound examination, suggesting the presence of a structural abnormality (25.2%). Invasive sampling was performed in the remaining 9.4% for various other reasons. The maternal blood was split into two parts. Half was subject to microarray and the other half was analyzed with standard karyotype.

In 98.8% (4340 patients), microarray was successfully completed. When a duplication or micro-deletion was found that had clinical significance (meaning it encompassed a region that previously had been associated with a documented phenotypic abnormality), this variation was deemed to be “pathological,” and it was reported directly to the patient. If the copy number variant was not associated with a known abnormality, it was labeled as “benign.” All others were individually reviewed by a committee of genetic experts who then separated each case out into a “likely benign” or “potentially significant” copy number variant.

All autosomal (7.4%) and sex chromosome (1.3%) aneuploidies detected by standard karyotype were also identified by microarray, including all unbalanced rearrangements. Importantly, in samples exhibiting normal karyotypes, the microarray picked up an additional 6% of clinically relevant deletions and duplications in fetuses with structural abnormalities and another 1.7% of re- arrangements in fetuses whose mothers had invasive testing for advanced maternal age or non-reassuring screening. The microarray did not diagnose balanced translocations or any of the 13 cases of triploidy (three of whom had no abnormal ultrasound signs at the time of CVS). After expert review, these extra puzzling genetic variations (detected by micrioarry) were reduced to a mere 1.5% that remained “uncertain.”

Commentary

Microarray greatly increases the diagnostic spectrum of prenatal diagnosis. By including previously undetected copy number variants, clinically meaningful conditions, like autism-spectrum, can be identified. Since around 1% of U.S. children have been diagnosed with this condition, this study will likely get the attention of the public. Undoubtedly, this will result in a need for providers to increase the scope of their pre-test and post-test counseling. Not only will providers need to include a careful explanation of the risks and benefits of invasive testing but also the potential for expanded results beyond the classic aneuploidic conditions like trisomy 21 and Turner X0. Providers will now be expected to understand, counsel, and interpret results for an expanded number of conditions — some with “uncertain” clinical meaning and some “clinically benign” — that may provoke anxiety in expecting parents. It is quite clear that patients whose fetuses have structural abnormalities have a reason for microarray analysis, since approximately 6% of these fetuses, despite a normal standard karyotype, will have clinically significant micro-deletions or translocations.

However, a potential can of worms awaits the public. One limitation of microarray is that 1.7% of those having positive screening for Down syndrome or advanced maternal age “had clinically significant copy number variants.” Some may interpret this to mean that, potentially, one in 60 patients in the overall population with structurally normal fetuses may have a “positive” microarray result — raising alarm and concern in most patients. Since the American College of Obstetricians and Gynecologists has recommended that all patients, regardless of risk, should be offered the option of invasive sampling, this may result in a large increase in demand for amniocentesis and CVS before we are ready to use this new diagnostic tool.

Fortunately, this may be short-lived because progress is already being made into exploring the fetal genome through microarray in maternal blood.3

References

  1. Hobbins JC. Fetal DNA testing for aneuploidy detection. Ob Gyn Clinical Alert 2012;29:5-8.
  2. Wapner RJ, et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med 2012;367:2175-2184.
  3. Fan HC, et al. Non-invasive prenatal measurement of the fetal genome. Nature 2012;487:320-324.