A comprehensive microarray prenatal study: efficacy for both copy number and copy neutral changes. S. Schwartz1, R. Pasion1, H. Cabral1, R. Burnside1, I. Gadi1, E. Keitges2, L. Kline1, V. Jaswaney1, K. Phillips1, H. Risheg2, B. Rush1, J. Shafer1, H. Taylor1, J. Tepperberg1, P. Papenhasuen1 1) Laboratory Corporation of America, Research Triangle Park, NC; 2) Dynacare/Laboratory Corporation of America, Seattle, WA.

   Utilizing an Affymetrix platform we have now performed over 8500 prenatal ancillary analyses, the largest to date and only major study employing a platform that includes SNPs. The prenatal reporting thresholds were 1 Mb for deletions and 2 Mb for duplications. However, alterations as low as 50 kb were reported when significant pathogenic genes were involved. Results from this work revealed that ~4.8% of over 4,000 pregnancies ascertained with ultrasound (US) had pathogenic copy number changes. This frequency varied based on the specific US anomaly, ranging from ~1.9% for soft markers to ~9.5% for multiple abnormalities. The indication of an US heart defect was associated with copy number changes in ~9.7% of the analyses (with fewer than 30% due to 22q deletions). The frequency of UPD and consanguinity in patients with any US abnormality was ~3.6%; but, prenatal analyses with multiple US anomalies correlated with consanguinity in ~6.0% of the studies. The frequency of pathogenic copy number changes in chromosomally normal AMA/anxiety patients was ~1.1%. These studies have not only proven the importance and efficacy of utilizing a platform with genotyping capabilities, but have yielded some illuminating results including: (a) The importance of establishing clear reporting cut-offs, which were based on the previous analysis of almost 50,000 pediatric arrays; (b) The frequency of prenatal detection of variants of unknown significance was only 1.0-1.3%; (c) The recognition of changing referral patterns for prenatal array analysis with the frequency of AMA/anxiety referral studies which has almost doubled since the NICHD study (18.5% to 32.7%); (d) The usefulness of finding pathogenic copy number abnormalities not only in pregnancies ascertained with US anomalies, but in all patients; (e) The elevated frequency of consanguinity in referral due to US abnormalities suggests the causal importance of autosomal recessive diseases; (f) The technology was also very beneficial for resolving structurally abnormal chromosomes; (g) The analysis of cells in culture longer than 2 weeks revealed an increased frequency of apparent culture artifacts which must be reported appropriately; (h) Lastly, these studies showed that a firm background in interpreting pediatric array variation is necessary since both new pathogenic syndromes and consanguinity have been detected prenatally at a higher frequency than expected and need to be reported in the appropriate clinical context.

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