Two cases of Wolf-Hirshhorn syndrome detected by noninvasive prenatal testing (NIPT)

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ConClusion NIPT has rapidly become a part of the standard of care for aneuploidy testing in high-risk pregnancies. We demonstrated initial expansion of this technology by effectively detecting certain microdeletions. We also continue to augment the number of conditions we are screening, which now includes Wolf-Hirshhorn and other microdeletions of significant clinical relevance. This abstract provides evidence and further supports broadening the capabilities of noninvasive testing to detect subchromosomal deletion events, as well as the potential to derive fetal karyotypes in the future. Results Wolf-Hirschhorn syndrome (WHS; OMIM 194190) is caused by a deletion of genetic material near the end of the short (p) arm of chromosome 4. The WHS critical region is localized to 4p16.3 and includes the genes WHSC1, LETM1, and MSX1. This condition is characterized by distinctive facial features, growth delays, intellectual disability, hearing loss, and seizures. Slow growth begins before birth, and affected infants tend to have problems feeding and gaining weight. This is a rare diagnosis, with a frequency of 1 in 50,000 births. For unknown reasons, WHS occurs in about twice as many females as males. 31-41501R1.0_0315 intRoduCtion Since its launch in late 2011, NIPT has become a routine practice in the management of pregnancies at high risk of fetal aneuploidy. The initial focus of NIPT was on whole chromosomal aneuploidies, which account for a smaller percentage of chromosome abnormalities when compared to microdeletions and microduplications. As the experience with this technology has grown, so have the improvements in the bioinformatics processes. Sequenom Laboratories™ has developed a low coverage whole genome sequencing algorithm to detect microdeletions. Our first deletion series (1p36, 5p, 15q, and 22q11) was launched in October 2013 followed by additional content (4p, 8q, and 11q) added in July 2014. MetHods Maternal plasma samples submitted to Sequenom Laboratories for MaterniT21® PLUS testing are subjected to DNA extraction and library preparation, followed by whole genome massively parallel sequencing as described by Jensen et al. Sequencing data was analyzed using a novel algorithm (Zhao et al.) to screen for subchromosomal deletions. Results Case 1 is a high-risk pregnancy due to multiple ultrasound findings presenting at 19wk 5day gestation. NIPT was ordered to include our Enhanced Sequencing Series and a 34 Mb deletion of 4p16.3p14 was detected and reported. Additionally, a 14.9 Mb duplication was observed at 4q34.1q35.2. The patient underwent amniocentesis and both events were confirmed by microarray analysis. A second Case (Case 2) was identified during a retrospective analysis of data obtained prior to the launch of our expanded microdeletion series. Case 2 is a primipara at 14wk 3day gestation with a serum screen result positive for trisomy 21. Although no ultrasound findings were observed and NIPT had been reported negative, the patient elected amniocentesis and microarray analysis identified a 4p16.3p15.1 deletion. The sequencing data from this patient were reanalyzed using the current algorithm which correctly identified the 4p deletion observed by microarray testing. RefeRenCes 1. Jensen TJ, Zwiefelhofer T, Tim RC, et al. High-throughput massively parallel sequencing for fetal aneuploidy detection from maternal plasma. PLoS One. 2013;8(3):e57381. doi: 10.1371/journal.pone.0057381. Epub 2013 Mar 6. 2. Zhao C, Deciu C, Ehrich M, et al. Detection of fetal subchromosomal abnormalities by sequencing circulating cell-free DNA from maternal plasma. PLoSone. In press. Case 1 This case was submitted for NIPT testing at 19wks 3days gestation. A chromosome 4p deletion consistent with Wolf-Hirschhorn syndrome was detected and this result was reported to the patient's physician. Top ideogram displays the 34 Mb deletion observed at 4p16.3p14; bottom ideogram highlights an additional 14.9 Mb duplication observed at 4q34.1q35.2. Both of these events were confirmed by microarray analysis of DNA purified from amniocytes. Case 2 This case was reported at 14wks 3days gestation as a normal fetus prior to the launch of our expanded microdeletion series. Amniotic fluid was collected at 19wks 1day due to additional ultrasound findings and submitted for karyotype and microarray analysis. Microarray analysis revealed a 27.85 Mb deletion on 4p16.3p15.1. A retrospective analysis of the original sequencing data generated from the MaterniT21 Plus assay using algorithms that now detect subchromosomal events confirmed the presence of this event as shown below. two cases of Wolf-Hirshhorn syndrome detected by noninvasive prenatal testing (niPt) Thomas Monroe 1 , Nilesh Dharajiya 2 , Julie Jesiolowski 1 , Theresa Boomer 2 , Ron McCullough 2 , Chen Zhao 2 , Paul Oeth 2 , Juan-Sebastian Saldivar 2 1 Sequenom Laboratories™, Morrisville, NC ; 2 Sequenom Laboratories™, San Diego, CA

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