Karyotype versus Microarray Testing for Genetic Abnormalities after Stillbirth

Abstract

Background Genetic abnormalities have been associated with 6 to 13% of stillbirths, but the true prevalence may be higher. Unlike karyotype analysis, microarray analysis does not require live cells, and it detects small deletions and duplications called copy-number variants. Methods The Stillbirth Collaborative Research Network conducted a population-based study of stillbirth in five geographic catchment areas. Standardized postmortem examinations and karyotype analyses were performed. A single-nucleotide polymorphism array was used to detect copy-number variants of at least 500 kb in placental or fetal tissue. Variants that were not identified in any of three databases of apparently unaffected persons were then classified into three groups: probably benign, clinical significance unknown, or pathogenic. We compared the results of karyotype and microarray analyses of samples obtained after delivery. Results In our analysis of samples from 532 stillbirths, microarray analysis yielded results more often than did karyotype analysis (87.4% vs. 70.5%, P<0.001) and provided better detection of genetic abnormalities (aneuploidy or pathogenic copy-number variants, 8.3% vs. 5.8%; P = 0.007). Microarray analysis also identified more genetic abnormalities among 443 antepartum stillbirths (8.8% vs. 6.5%, P = 0.02) and 67 stillbirths with congenital anomalies (29.9% vs. 19.4%, P = 0.008). As compared with karyotype analysis, microarray analysis provided a relative increase in the diagnosis of genetic abnormalities of 41.9% in all stillbirths, 34.5% in antepartum stillbirths, and 53.8% in stillbirths with anomalies. Conclusions Microarray analysis is more likely than karyotype analysis to provide a genetic diagnosis, primarily because of its success with nonviable tissue, and is especially valuable in analyses of stillbirths with congenital anomalies or in cases in which karyotype results cannot be obtained. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.)

Microarray-based comparative genomic hybridization analysis in neonates with congenital anomalies: detection of chromosomal imbalances

“…To date, the largest newborn screening (in 20,126 unselected cases) using array-CGH analysis as a first-line test revealed that 87/20,126 (0.43%) of the neonatal cases had chromosomal imbalances (53 cases of aneuploidies, 23 deletions, and 11 duplications). 4 Reddy et al 14 reported the results of a population-based study of 532 stillbirths. In this sample, array-CGH analysis yielded more results than did karyotype analysis (87.4% vs. 70.5%), provided better detection of genetic abnormalities (aneuploidy or pathogenic CNVs, 8.3% vs. 5.8%), and also identified more genomic imbalances among 67 stillbirths with congenital anomalies (29.9% vs. 19.4%).…”

Comprehensive genetic analysis of pregnancy loss by chromosomal microarrays: outcomes, benefits, and challenges

“…[4][5][6][7][8][9][10][11] Fetal chromosomal abnormalities account for approximately 8-10% of intrauterine fetal demises occurring after 20 weeks of gestation and/or stillbirths occurring in the second or third trimester. 9,12 The etiologic analysis of pregnancy loss can provide important information for medical management, reproductive counseling, and supportive patient care. 4,13,14 Although fetal karyotyping has been used for many years to evaluate samples of products of conception (POCs), there are two primary limitations to this method.…”

“…The superior diagnostic power of CMA compared with karyotyping is well established in the pediatric and prenatal literature; however, exploration of the use of this technology for studying POC samples has been somewhat limited to date. 9,10,12,14,15,18,[20][21][22][23][24][25][26][27][28] Specifically, CMA is a particularly attractive technology for use in the study of POC samples because it is performed using extracted cellular DNA, significantly improving the likelihood of obtaining a result. Unlike karyotype analysis, CMA can even be performed on DNA extracted from formalin-fixed and paraffin-embedded tissues (FFPE), a process that is undergone by nearly every POC sample subjected to histopathological evaluation.…”

Molecular and Cytogenetic Analysis in Stillbirth: Results from 481 Consecutive Cases

“…the 23-kb duplication disrupting the MYH6 and MYH7 genes in a stillborn with atrial septal defect. Reddy et al [6] excluded all CNVs <500 kb in their analysis. Our finding illustrates the importance of evaluating all detected aberrations, regardless of size.…”

“…Since the introduction of CMA, submicroscopic aberrations have been shown to be associated with a number of conditions such as developmental delay, intellectual disability, congenital malformations and autism spectrum disorders [4,5]. The importance of such small aberrations has not yet been extensively studied in stillbirth, however a recent study by Reddy et al [6] showed that CMA increases the detection of chromosomal abnormalities considerably compared to karyotyping. Additionally, the technique does not require cell culture, and can hence be performed on DNA from macerated tissue.…”