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Abnormal ultrasound and increased yield of abnormal results with genome-wide cfDNA analysis

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Jenna Wardrop 1 , Marcos Gonzales 1 , Theresa Boomer 1 , Phillip Cacheris 1 , Eyad Almasri 1 , Ron McCullough 1 1 Sequenom Laboratories™, San Diego, CA 10% 48% 6% 22% 8% 6% Abnormal ultrasound and increased yield of abnormal results with genome-wide cfDNA analysis RESULTS Figure 3. Positive by submitted high risk indications Figure 1. Submitted high risk indications Figure 2. Abnormal results OBJECTIVE Cytogenetic anomalies currently screened by cfDNA constitute ~80% of karyotypic abnormalities (T21, T18, T13, SCA). 1 Ultra-sound anomalies are known to be associated with higher rates of chromosome anomalies, and include subchromosomal events throughout the genome. 2 The MaterniT® GENOME laboratory-developed test offers the novel capability of detecting genome wide events, greatly expanding the range of abnormalities detectable by cfDNA testing. Herein we describe our experience with the first 5,000 MaterniT GENOME tests. STUDY DESIGN Maternal blood samples submitted to Sequenom Laboratories™ for MaterniT GENOME testing were subjected to DNA extraction, library preparation, and whole genome massively parallel sequencing as described by Jensen et al. Sequencing data were analyzed using a novel algorithm to detect aneuploidies and sub chromosomal events 7 Mb and greater in size, as well as select microdeletions. 3 RESULTS The first 5,000 MaterniT GENOME tests had a positivity rate of 5.8%. Reasons for referral were notably different from those observed in "conventional" cfDNA testing, with ultrasound anomalies noted as an indication in nearly twice as many samples. 4 Approximately 32% of abnormal results reported would not have been identified by conventional cfDNA tests. CONCLUSIONS Genome-wide analysis of cfDNA allows for broad assessment of fetal chromosome anomalies, approximately one fifth of which may be missed with conventional noninvasive prenatal testing. CNVs constitute a significant portion of abnormal results related to ultrasound abnormalities in this cohort. In the first 5,000 samples the MaterniT GENOME test has identified whole chromosome aneuploidies or CNVs on every chromosome in the genome. 5 Correlation of specific anatomic abnormalities and chromosome aberrations is a topic of future study. For patients with ultrasound anomalies who decline invasive testing and request a cfDNA test, MaterniT GENOME offers the most comprehensive testing option currently available. REFERENCES 1. Baer, RJ et al. Detection rates for aneuploidy by first-trimester and sequential screening. Obstet Gynecol. 2015 Oct;126(4):753-9. doi: 10.1097/ AOG.0000000000001040 2. Wapner RJ et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med. 2012 Dec 6;367(23):2175-84. doi: 10.1056/ NEJMoa1203382. 3. Leowitz RB et al. Clinical validation of a non-invasive prenatal test for genome-wide detection of fetal copy number variants. Am J Obstet Gynecol. 2016 Feb. http://dx.doi.org/10.1016/j.ajog.2016.02.030 4. McCullough, R et al. Non-invasive prenatal chromosomal aneuploidy testing- clinical experience: 100,000 clinical samples. PLOS one. 2014 Oct. http://dx.doi.org/10.1371/journal.pone.0109173 5. McCullough R et al. Early clinical adoption and utilization of genome-wide NIPT. Poster session presented at: American College of Medical Genetics and Genomics Annual Clinical Genetics Meeting; 2016 Mar 8-12; Tampa, Fl. SEQUENOM®, MaterniT® and Sequenom Laboratories™ are trademarks of Sequenom, Inc. 31-41540R1.0_0616 N = 5000 Ordered Total 16% 32% 51% History Ultrasound +/- other indication(s) Ultrasound + AMA Ultrasound only Advanced Maternal Age Serum screen 0% 5% 10% 15% 20% 25% 1% 8% 11% 13% Trisomy 13/18/21 Sex Chromosomal Aneuploidies Microdeletions Complex del / dup Isolated del /dup Esoteric Trisomy Aneuploidy Subchromosomal CNV Microdeletion <7Mb First 5000 MaterniT Genome Results Positive n = 292 Positive by Indication Positive n = 292 Advanced Maternal Age Serum Screen Ultrasound Finding Personal History Other High Risk Multiple Reasons

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