Copy-number changes in prenatal diagnosis

Abstract

Until recently, the prenatal detection of genetic disease was available to only a subset of the pregnant population deemed to be at an increased risk for chromosomal abnormalities or, more rarely, other genetic disorders, based on family history, multiple-marker screening or ultrasound findings. Guided by recent data that indicate that screening for Down syndrome has improved and that risks of invasive procedures are smaller than previously ascertained, the American College of Obstetricians and Gynecologists has recommended that all women have access to invasive prenatal diagnosis. The parallel development of newer genetic diagnostic technologies, such as chromosomal microarray analysis, has made it feasible to simultaneously test for more conditions than was possible with standard karyotype analysis complemented by targeted fluorescence in situ hybridization or mutation detection for specific conditions. In the pediatric and adult population, chromosomal microarray analysis has already been thoroughly evaluated and is now recommended as a first-line diagnostic test for clinically suspected genetic disorders. In this article, we review the current status of array-based comparative genomic hybridization use for prenatal diagnosis and predict that, in the future, it will replace karyotyping as a first-line test for detecting chromosomal abnormalities in the prenatal setting.

Karyotype Versus Microarray Testing for Genetic Abnormalities After Stillbirth

“…However, the challenge of counseling couples about unpredictable outcomes is not new. 26 We observed a recurrent variant of unknown significance in a telomeric region of chromosome 19p13.3 (ranging in size from 632 to 930 kb) in eight stillbirths. This region is known to contain multiple benign variants as well as five loci in the OMIM database that have been associated with disease but not with stillbirth or developmental disorders.…”

“…However, inherited pathogenic variants should not be discounted as a cause of stillbirth because of their variable expressivity and incomplete penetrance. 8,26 Our ability to assess confined placental mosaicism, in which the fetus is genetically normal but the placenta is genetically abnormal, was limited.…”

“…Microarray analysis is more expensive than standard karyotype analysis, although its cost is expected to decrease 26 and may be offset by the higher yield of genomic abnormalities.…”

The introduction of arrays in prenatal diagnosis: A special challenge

“…Thus, one might argue that the use of genome-wide array in prenatal diagnostics should not be restricted to pregnancies with ultrasound abnormalities [Strassberg et al, 2011]. On the other hand, the interpretation of array results is challenging, especially in the absence of ultrasound abnormalities, as pathogenic CNVs that do not result in a phenotype detectable by ultrasound may sometimes be hard to distinguish from benign CNVs.…”

Chromosomal microarray analysis as a first-line test in pregnancies with a priori low risk for the detection of submicroscopic chromosomal abnormalities

“…However, the fact that only a minority of the submicroscopic abnormalities that are detected in postnatal patients with developmental delay/intellectual disability are accompanied by congenital abnormalities detectable by prenatal ultrasound, suggests the use of CMA in prenatal diagnostics not only for pregnancies with ultrasound abnormalities. 32 In the absence of specific guidelines and large-scale studies for different categories of indications, it has been suggested that CMA should be offered as an adjunction tool to selected groups of high-risk pregnancies (eg abnormal ultrasound findings and a normal conventional karyotype), using the technique as a second-line test only, after a standard karyotype. 25 Recently, the Canadian College of Medical Geneticists (CCMG) has discouraged the use of CMA in pregnancies at low risk for a structural chromosomal abnormality (eg advanced maternal age, positive maternal serum screen, previous pregnancy with a chromosomal abnormality or the presence of 'soft markers' on fetal ultrasound), motivating their position with the fact that CMA performed for the above categories of pregnancies would likely be associated with a low positive predictive value, since the vast majority of fetuses in these situations would be clinically unaffected.…”