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

Abstract

We present the nature of pathogenic SNP array findings in pregnancies without ultrasound (US) abnormalities and show the additional diagnostic value of SNP array as compared with rapid aneuploidy detection and karyotyping. 1,330 prenatal samples were investigated with a 0.5-Mb SNP array after the exclusion of the most common aneuploidies. In 2.7% (36/1,330) of the cases, pathogenic chromosome aberrations were found; a microscopically detectable abnormality in 0.7% and a submicroscopic aberration in 2%. Our results show that in addition to the age- or screening-related aneuploidy risk, in pregnancies without US abnormalities, there is a risk of 1:148 (9/1,330) for a (sub)microscopic abnormality associated with an early-onset often severe disease, 1:222 (6/1,330) for a submicroscopic aberration causing an early-onset disease, 1:74 (18/1,330) for carrying a susceptibility locus for a neurodevelopmental disorder, and 1:443 (3/1,330) for a late-onset disorder (hereditary neuropathy with liability to pressure palsies in all three cases). These risk figures are important for adequate pretest counseling so that prospective parents can make informed individualized choices between targeted prenatal testing and broad testing with SNP array. Based on our results, we believe if invasive testing is performed, SNP array should be the preferred cytogenetic technique irrespective of the indication.

Is prenatal cytogenetic diagnosis with genomic array indicated in pregnancies at risk for a molecular or metabolic disorder?

“…In three out of 148 (2%) of the cases unexpected unbalanced chromosome aberrations were found: trisomy 21 and two submicroscopic pathogenic findings (a 1.7Mb 7q11.23 microdeletion associated with Williams-Beuren syndrome and a 3.14 Mb 1q21.1 microdeletion (including the TAR region and distal 1q21.1 microdeletion), a SL for neurodevelopmental disorders and also associated with an increased risk for cardiac malformations). These results are consistent with our previous estimate 5 and show that two out of three imbalances would not be diagnosed by both rapid aneuploidy testing and karyotyping, justifying the use of the array technique for cytogenetic studies in these pregnancies.…”

“…Our recently published data 5 were consistent with those in prior publications; 0.5% of fetuses had a pathogenic submicroscopic variation associated with an early-onset disorder, and 0.2% of fetuses had a microscopically visible aberration resulting in an abnormal fetal phenotype. Therefore, fetuses without ultrasound anomalies have a background population risk of 1 in 150 (0.7%) for an unbalanced chromosome aberration (either microscopically visible or submicroscopic) associated with an early-onset disorder.…”

“…Some large-scale studies showed a significant percentage (0.5%) of pathogenic submicroscopic findings in pregnancies tested due to advanced maternal age or abnormal first-trimester screening. [3][4][5] This figure excludes cases of susceptibility loci (SL), which are phenotypically heterogeneous and have a reduced penetrance.…”

“…8 Our previous study evaluated the frequency of microscopic and submicroscopic copy-number variations in patients presenting for prenatal diagnostic testing for a variety of indications. 5 To evaluate the utility of array testing in patients with no risk factors for karyotypic abnormalities, we reanalyzed the data. We were especially interested in whether the risk of 1 in 150 for an unbalanced chromosome aberration also applies to pregnancies referred for molecular or biochemical testing that are not at increased risk for a cytogenetic abnormality.…”

Prenatal SNP array testing in 1000 fetuses with ultrasound anomalies: causative, unexpected and susceptibility CNVs

“…All pathogenic findings (including CAU, UD, SL and IF) were reported to patients. 6,18 For the purpose of this paper, we have categorized chromosome aberrations according to their size and depending on whether they were (or could be) detected by RAD. The following categories are recognized: RAD detectable, microscopic abnormalities and submicroscopic abnormalities.…”