Experience With Microarray-Based Comparative Genomic Hybridization for Prenatal Diagnosis in Over 5000 Pregnancies

Abstract

Objective To demonstrate the usefulness of microarray testing in prenatal diagnosis based on our laboratory experience.Methods Prenatal samples received from 2004 to 2011 for a variety of indications (n = 5003) were tested using comparative genomic hybridization-based microarrays targeted to known chromosomal syndromes with later versions of the microarrays providing backbone coverage of the entire genome.Results The overall detection rate of clinically significant copy number alterations (CNAs) among unbiased, nondemise cases was 5.3%. Detection rates were 6.5% and 8.2% for cases referred with abnormal ultrasounds and fetal demise, respectively. The overall rate of findings with unclear clinical significance was 4.2% but would reduce to 0.39% if only de novo CNAs were considered. In cases with known chromosomal rearrangements in the fetus or parent, 41.1% showed CNAs related to the rearrangements, whereas 1.3% showed clinically significant CNAs unrelated to the karyotype. Finally, 71% of the clinically significant CNAs found by microarray were below the resolution of conventional karyotyping of fetal chromosomes.Conclusions Microarray analysis has advantages over conventional cytogenetics, including the ability to more precisely characterize CNAs associated with abnormal karyotypes. Moreover, a significant proportion of cases studied by array will show a clinically significant CNA even with apparently normal karyotypes.

Benefits and Burdens of Using a SNP Array in Pregnancies at Increased Risk for the Common Aneuploidies

“…The incidence of submicroscopic unexpected diagnoses in normal fetuses (0.6%) seems to be comparable to that in abnormal fetuses (ca. 0.5% in our center; Srebniak et al, submitted for publication), which most probably represents the background risk for a submicroscopic chromosome aberration in the general population [Shaffer et al, 2012a]. The fact that part of the unexpected findings was microscopically visible (0.2%) illustrates that unexpected diagnoses were also seen in the prearray era and therefore are not new in the field of prenatal diagnosis.…”

“…Since July 2012, we replaced karyotyping by SNP array for all indications, mainly because of the proven increased detection of pathogenic chromosome aberrations, at least in cases with US abnormalities, while knowing that many microdeletion syndromes will not produce abnormal features detectable by US. Moreover, it was already postulated before that there may be a background risk for a submicroscopic chromosome aberration in the general population [Shaffer et al, 2012a]. To maximize the detection of pathogenic findings and at the same time minimize the detection of VUS, we decided to analyze at a lower resolution of ß0.5 Mb for all cases without US anomalies, whereas we use ß0.15 Mb in cases with US abnormalities, as we published previously [Srebniak et al, 2013].…”

Application of a new molecular technique for the genetic evaluation of products of conception

“…This technique has a major advantage of being able to detect cryptic imbalances that, however, in miscarriages have a modest incidence (~6%) in respect to gross chromosome imbalances. [24][25][26][33][34][35] Fluorescence in situ hybridization offers rapid diagnosis of polyploidies as well as common monosomies and trisomies for chromosomes 13,15,16,18,21,22, X and Y, which account for approximately 80% to 95% of all chromosome abnormalities in POC samples 36 (present study); however, quality assurance probes are expensive, and the technique is still labor-intensive. Quantitative fluorescent PCR is lowly dependent on the DNA quality and detects polyploidies as well as all common monosomies and trisomies (13, 18, 21, X and Y).…”

“…In the case of normal result and sufficient DNA quality, a 'third-tier' CMA analysis can be applied to detect cryptic imbalances having an estimated incidence of~6% in POC specimens (combined data from published studies: 45/709; 6.3%). [24][25][26][33][34][35] CMA and microsatellite analysis can also be applied directly after a normal KaryoLite ™ result in case of cell growth failure. The proposed workflow should be modified in case of placental villi or tissues of unidentifiable origin.…”

Identification of dosage‐sensitive genes in fetuses referred with severe isolated congenital diaphragmatic hernia

“…This diagnostic yield is higher than the~6% rate, which is observed in recent studies for the routine diagnostic use of chromosomal microarrays for pregnancies with ultrasound anomalies. 86,87 We therefore advocate the use of chromosomal microarrays for CNV detection in the prenatal diagnosis of fetuses with isolated or non-isolated CDH. Despite the reduced penetrance of CDH, arrays have proven to be a powerful approach in identifying genes underlying both isolated and syndromic cases of CDH.…”