Whole genome oligonucleotide-SNP arrays in prenatal diagnosis: advancement in identification of clinically significant chromosomal abnormalities. T. Sahoo, L. P. Ross, K. A. Kopita, L. W. Mahon, J.-C. J. Wang, M. Hemmat, B. T. Wang, F. Z. Boyar, M. Haddadin, M. M. Elnaggar, R. Owen, A. Anguiano Quest Diagnostics Nichols Institute, San Juan Capistrano, CA.

   Identification of chromosomal abnormalities has been significantly enhanced by the utilization of microarray-based technologies. Chromosomal microarray-based (CMA) testing of postnatal samples for detection of pathogenic copy number alterations in patients with developmental delay, congenital anomalies, autism and intellectual disability has proven invaluable. The introduction of CMA for prenatal diagnosis has been more recent. Since the implementation of CMA for prenatal testing at Quest Diagnostics, over 1000 samples have undergone testing. Of the 1000 samples being reported here, 350 were tested utilizing a targeted BAC arrayCGH platform and the remaining 650 with Affymetrix 6.0 or the Cytoscan HD platform. Abnormal ultrasound findings were the predominant clinical indication (67% of cases). Clinically significant copy number alterations (CNAs) were reported in 92 cases (9.2%), findings of unclear clinical significance in 94 (9.4%) and 814 (81.4%) cases with no reportable copy number alterations. Significantly, 60 of the 92 cases (65%) with clinically significant CNA had an abnormal chromosome karyotype and 26 (28%) had normal karyotype analysis; in contrast only 8 of the 94 with CMA findings of unclear significance had an abnormal karyotype. Clinically significant CMA findings, in addition to confirming whole chromosome aneuploidies, provided accurate and explicit identification of marker chromosomes (11% cases), accurate characterization of unbalanced translocations (17% cases), identification and structure of submicroscopic deletions and duplications including complex mosaic abnormalities (20% cases) and, most significantly, enabled identification of recurrent pathogenic microdeletion-microduplication syndromes in 19 cases (21%; 19 of the 26 cases with a normal karyotype analysis). Four of the 94 cases with findings of unclear significance harbored multiple segments of homozygosity suggestive of parental relatedness and predicting an increased risk for recessive Mendelian disorders. Therefore, implementation of CMA as a primary diagnostic tool in prenatal testing has profoundly improved our ability to detect clinically significant alterations, particularly in cases with abnormal ultrasound findings. Our experience confirms and incrementally improves upon the findings of other laboratories, lending further support to CMA as a first-tier test for prenatal diagnosis in high-risk pregnancies, especially those with abnormal ultrasound results.

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