Clinical experience of trisomy 16 and 22, and microdeletion detection by noninvasive prenatal testing (NIPT)

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22q11 deletion 8q deletion (Langer-Giedion) Cri-du-chat (5p-) 15q11 deletion (PW/AS) 1p36 deletion 4p deletion (Wolf- Hirschhorn) 11q deletion (Jacobsen) Condition total Confirmed Strongly SuSpeCted no information falSe poSitive ppv* (lower bound) ppv** (upper bound) t16 55 9 18 15 13 49.1% 76.4% t22 33 4 15 7 7 57.6% 78.8% 22q11 32 23 8 1 0 96.9% 100.0% 5p 6 3 1 0 2 66.7% 66.7% 15q 9 8 1 0 0 100.0% 100.0% 1p36 5 3 0 1 1 60.0% 80.0% 4p 1 1 0 0 0 100.0% 100.0% 11q 1 1 0 0 0 100.0% 100.0% 8q 1 0 1 0 0 100.0% 100.0% total 143 52 44 24 23 - - ReSuLtS In testing more than 159,000 samples, the MaterniT21® PLUS test generated results consistent with 55 cases of Trisomy 16, 33 cases of Trisomy 22, 32 cases of 22q11 deletion syndrome, 9 cases of 15q deletions associated with Prader Willi/Angelman syndrome, 5 cases of 1p36 deletions, 6 cases of 5p deletions associated with Cri-du-Chat syndrome, 1 case of 4p deletion associated with Wolf-Hirschhorn syndrome, 1 case of 11q deletion associated with Jacobsen syndrome, and 1 case of 8q deletion associated with Langer-Giedion syndrome. A handful of maternal 22q deletions have been detected, with a 50% chance of a concomitant fetal deletion, this is a known limitation of NIPT. Another biological limitation of the technology is the incidence of placental mosaicism, specifically for Trisomy 16 and Trisomy 22. The overall positive predictive value for each subchromosomal aberration ranged from 60% to nearly 100% for cases with follow-up information. The total confirmed false positive rate was 0.01%; the rate was 0.02% when results with no clinical follow-up were assumed to be false positives. ConCLuSion Initially used for detecting trisomy 21 only, MaterniT21® PLUS has advanced into a LDT for also detecting trisomy 18, trisomy 13, and sex chromosome aneuploidies. Here, we demonstrate continued expansion of the technological capabilities to effectively detect microdeletions and two additional rare trisomies. Table 1. Outcome data for the enhanced sequencing series *(True Positive)+(Suspected)+(No Information)/Total **(True Positive)+(Suspected)/Total updated clinical experience of trisomy 16 and 22, and microdeletion detection by noninvasive prenatal testing (niPt) 31-41515R1.0 0715 intRoduCtion Building on the success and experience of analyzing circulating cell free DNA for trisomy 21, 18 and 13 in >340,000 cases, we expanded the technology used in our laboratory developed test (LDT) to investigate subchromosomal deletion and duplication events. A novel algorithm to identify fetal microdeletion and microduplication events in maternal plasma has been developed by Sequenom Laboratories TM . We used this approach to identify microdeletions 5pdel, 22q11del, 15qdel and 1p36del, 4pdel, 11qdel, 8qdel, as well as trisomies 16 and 22. MetHodS Maternal blood samples submitted to Sequenom Laboratories™ for MaterniT21® PLUS testing were subjected to DNA extraction, library preparation, and whole genome massively parallel sequencing as described by Jensen et al. 1 Sequencing data were analyzed using a novel algorithm to detect trisomies and other microdeletions. 2 Jenna Wardrop 1 , Nilesh Dharajiya 1 , Thomas J. Monroe 2 , Julie Jesiolowski 2 , Theresa Boomer 1 , Eyad Almasri 1 , Ron McCullough 1 1 Sequenom Laboratories™, San Diego, CA, 2 Sequenom Laboratories, Morrisville, NC RefeRenCeS 1. Jensen TJ1, 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. 3. Wolstenholme J. Prenat Diagn. 1996;16(6):511-24. 4. Wilson DI, Cross IE, Wren C, et al. Am J Hum Genet. 1994;55:A169. 5. Higurashi M, Oda M, Iijima K, et al. Brain Dev. 1990;12:770-773. 6. Niebuhr E. Hum Genet. 1978; 44: 227-275. doi: 10.1007/BF00394291. 7. Driscoll DJ, Miller J, Schwartz S, et al. Available from: 8. Clayton-Smith J, Pembrey ME. J Med Genet. 1992;29:412-5. 9. Slavotinek A, Shaffer LG, Shapira SK. Monosomy 1p36. J Med Genet. 1999;36:657-63. 10. Maas NM C, Van Buggenhout G, Hannes F, et al. Genotype-phenotype correlation in 21 patients with Wolf-Hirschhorn syndrome using high resolution array comparative genome hybridization (CGH). J Med Genet. 2008;45:71-80. 11. Mattina T, Perrotta CS, Grossfeld P. Jacobsen syndrome. Orphanet J Rare Dis. 2009;4:9. Doi:10.1186/1750-1172-4-9. ReSuLtS

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