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Identification of 22q11 microdeletions by noninvasive prenatal testing (NIPT) - the clinical experience

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1.45 MB 0.75 MB 3.15 MB 1.55 MB 1.55 MB 1.55 MB 1.55 MB 0.5 MB 31-41514R1.0 0515 IntroductIon NIPT for fetal aneuploidies has become routine practice in pregnancy management. Its accuracy and ease of administering a simple blood test has resulted in widespread adoption. A genome-wide approach to NIPT enables detecting subchromosomal events by employing a novel algorithm that uses sequencing data. The output for detected fetal microdeletion events is akin to data derived from conventional microarray analysis of invasively sampled DNA. Here we report our observations with 32 clinically identified cases with 22q11 deletions. MaterIals and Methods Maternal blood samples submitted to Sequenom Laboratories were subjected to DNA extraction and library preparation followed by whole genome massively parallel sequencing as described by Jensen, et al. 1 Jenna Wardrop 1 , Juan-Sebastian Saldivar 1 , Thomas Monroe 2 , Theresa Boomer 1 , Julie Jesiolowski 2 , Jennifer Hume 1 , Nilesh Dharajiya 1 , Ron M McCullough 1 1 Sequenom Laboratories™, San Diego, CA, United States, 2 Sequenom Laboratories, Morrisville, NC, United States cases Identification of 22q11 microdeletions by noninvasive prenatal testing (nIPt) – the clinical experience Figure 1: Classification of 22q11 clinical feedback Classification breakdown of clinical follow up on 32 22q11 cases resulted with NIPT Identified cases of 22q11 via NIPT 32 Maternal only 9 Fetal only 9 Both Maternal & Fetal 3 Maternal only 1 Fetal only 6 Both Maternal & Fetal 0 Strongly suspected 7 False positive 0 No supporting evidence 4 True positive 21 Figure 2: 22q11 Fetal cases Examples of confirmed or suspected fetal only cases of 22q11 Figure 3: 22q11 Maternal cases Examples of confirmed or suspected maternal cases of 22q11 Tetralogy of Fallot, pregnancy ongoing. Tetralogy of Fallot noted on ultrasound. Confirmatory testing declined, final outcome unknown. Tetralogy of Fallot noted on ultrasound. Microdeletion confirmed by FISH. Maternal seizure disorder, learning difficulties, and dental problems. Fetus normal. 2-vessel cord, possible club foot, no cardiac abnormality detected. Amnio declined, final outcome unknown. Confirmatory testing declined, fetal demise. Maternal events are called when a majority of the detected DNA contains the event. Deletion events are highlighted in the trace when identified by the algorithm. clInIcal Feedback results The MaterniT21® PLUS test identified 32 cases with a 22q11 deletion (0.5 – 3.15 Mb) between 11/1/13 and 11/1/14. We solicited clinical feedback for all 32 cases resulted, Figure 1. Based on the feedback received as of 1/15/2015 we categorized the results as: • True positive, cases with invasive test/birth outcome confirmation (n=21) • Strongly suspected, cases with ultrasound or clinical phenotypes supporting 22q11 (n=7) • False positive, cases with invasive test/birth outcome discordance (n=0) • No supporting evidence to date, absence of maternal or fetal phenotypes, or results from further testing are pending (n=4) Cases were further separated into fetal only, maternal only, or both fetal and maternal. Twenty- one cases were confirmed by subsequent invasive testing with nine as fetal only (Figure 2), nine maternal only (Figure 3), and three both fetal and maternal. Seven other cases were strongly suspected and had clinical findings of complex heart defects or Tetralogy of Fallot consistent with the NIPT result. Six of the suspected cases were fetal only and one was maternal only. Confirmatory testing in these cases was either declined or pending. In four additional cases, no clinical signs were identified and outcomes were pending. No confirmed false positives have been identified. One of the confirmed cases was a twin gestation where one twin was positive for the 22q deletion. Additionally, a 22q deletion was detected in the mother who has a history of developmental delay and phonation abnormality suggestive of a laryngeotracheal anomaly, concordant with the clinical presentation of 22q deletion syndrome. conclusIons It is imperative when testing for rare conditions, such as 22q11 deletions, that NIPT tests perform with the utmost specificity to result in high positive predictive values. By using a genome-wide sequencing approach, we have demonstrated that this objective is achievable. This abstract provides further evidence and support to broaden the scope of noninvasive testing to detect sub-chromosomal deletion/duplication events and the potential to derive fetal karyotypes in the future. reFerences 1. Jensen TJ, Zwiefelhofer T, Tim RC, Džakula Ž, Kim SK, et al. (2013) High-Throughput Massively Parallel Sequencing for Fetal Aneuploidy Detection from Maternal Plasma. PLoS ONE 8(3):e57381. doi:10.1371/ journal.pone.0057381

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