Prenatal whole genome SNP array diagnosis as a first-line test: nature and prevalence of abnormal results in phenotypically normal and abnormal fetuses. F. A. T. de Vries, M. I. Srebniak, L. C. P. Govaerts, K. E. M. Diderich, R. J. H. Galjaard, A. M. S. Joosten, A. R. M. Van Opstal Clinical Genetics, ErasmusMC, Rotterdam, Netherlands.

   Background: After initially applying SNP array in selected fetuses with ultrasound (US) abnormalities, since June 2011, we routinely perform array analysis in all cases of US abnormalities and since July 2012 in all samples that we receive in our laboratory for prenatal cytogenetic studies, irrespective of the indication. Here we show the nature and prevalence of abnormal array results in cases with and without US anomalies. Methods: After excluding the most common trisomies and triploidy by rapid aneuploidy detection (RAD), we performed HumanCytoSNP-12 (Illumina) array on uncultured cells of 1047 cases with fetal ultrasound anomalies and of 1408 cases of uneventful pregnancies. Clinically relevant array results were classified as proposed before in causative findings (CAU) (i.e. fitting the indication/phenotype), unexpected diagnoses (UD) (i.e. NOT fitting the indication/phenotype) and susceptibility loci (SL) for neurodevelopmental disorders (Srebniak et al., 2013, Eur J Hum Genet.; doi: 10.1038/ejhg.2013.254). Results: In 7.4% (77/1047) of fetuses with US anomalies pathogenic array findings were detected, a microscopically detectable abnormality in 1.8% and a submicroscopic aberration in 5.6%. In 2.9% (40/1408) of cases without US abnormalities, pathogenic chromosome aberrations were found, a microscopically detectable abnormality in 0.9% and a submicroscopic aberration in 2%. The prevalence of submicroscopic UD in both groups of fetuses was ~0.5% and mainly involved early-onset untreatable diseases. The prevalence of SL for neurodevelopmental disorders was twice as high in fetuses with US (2.6%) as compared to phenotypically normal fetuses (1.3%). Conclusion: SNP array testing is an asset to prenatal cytogenetic diagnosis, as is demonstrated by the detection of submicroscopic pathogenic chromosome abnormalities in cases with and without US anomalies. Apart from SL, these submicroscopic aberrations account for an extra 3% (abnormal fetuses) and 0.7% (normal fetuses) of clinically relevant aberrations. Therefore, array should be a first-tier prenatal cytogenetic test for all indications.

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