Prenatal Diagnosis of Chromosome Abnormalities: Past, Present, and Future

Abstract

For decades, conventional chromosome analysis using G-banded karyotyping has been the gold standard for detecting cytogenetic abnormalities in fetuses for prenatal diagnosis and pregnancy loss. Although chromosome studies easily identify such chromosome abnormalities as aneuploidy (gain or loss of an entire chromosome), balanced rearrangements, and large unbalanced structural rearrangements, they have limited resolution. Pathogenic copy number changes smaller than approximately 5–10 Mb are not detectable; however, recent advances in chromosomal microarray (CMA)2 analysis now allow the detection of chromosomal deletions and duplications at much higher resolutions (down to only a few kilobases, depending on the microarray), producing a higher diagnostic yield. In fact, a recently published study that compared standard karyotyping with postnatal CMA testing for patients with unexplained developmental delay, autism spectrum disorders, or multiple congenital anomalies demonstrated an increased diagnostic yield of about 12%–15% with CMA analysis, vs. 4% with karyotyping. These findings led to the recommendation by the American College of Medical Genetics that CMA testing replace chromosome analysis as the first-tier test for such patients (1, 2). Given these findings in the postnatal setting, the incremental diagnostic yields of CMA analysis and chromosome analysis are now being evaluated for prenatal genetic testing. Recent publications in the New England Journal of Medicine have described approaches to answering this question, not only with prenatal samples (3) but also with stillbirths (defined as pregnancy loss at or after 20 weeks' gestation) (4). The multicenter study by Wapner et al. successfully analyzed 4182 samples of amniotic fluid and chorionic villi with both chromosome and CMA analysis (3). The women were tested for indications that included advanced maternal age, a positive result in maternal-serum screening, and fetal anomalies detected on ultrasonography. CMA was equally efficacious in identifying all aneuploidies and unbalanced rearrangements that had been identified by karyotyping. …