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Expanding noninvasive prenatal testing (NIPT) for screening of unbalanced translocations

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Expanding noninvasive prenatal testing (NIPT) for screening of unbalanced translocations CASES Indication: Increased NT; maternal aunt with known balanced t(11;22). MaterniT® GENOME result: 18.4Mb gain of chromosome 11(q23.3-q25) and 3.0Mb gain of chromosome 22(q11.1-q11.21), as displayed in the upper and lower ideogram, respectively. Result is suggestive of an unbalanced translocation. Maternal karyotype confirmed balanced t(11;22). Amnio FISH and karyotype confirmed 47,XX+22,der(22)t(11;22) (q23;q11.2)mat, consistent with Emanuel syndrome. Chromosome 11 Chromosome 16 Chromosome 4 Chromosome 22 Chromosome 5 Chromosome 18 Above image represents a MaterniT GENOME report including detailed comments and ideograms of events. Indication: AMA MaterniT® GENOME result: 60.4Mb gain of chromosome 4(q28.2-q35.2) and 35.15Mb gain of chromosome 18(p11.32-q12.2), as displayed in the upper and lower ideogram, respectively. Holoprosencephaly known to provider prior to result disclosure. Amniocentesis resulted as 47,XY,+18,add(18)(q21.3). Pregnancy was subsequently lost. Maternal karyotype confirmed balanced t(4;18). Additional material on amniocentesis is expected to be from chromosome 4. Fetal karyotype updated accordingly, 47,XY,+18,der(18)t(4;18)(q28.2;q12.2)mat. INTRODUCTION Traditional noninvasive prenatal testing (NIPT) has proven to be a reliable screen for many high- risk pregnancies. However couples with familial translocations have limited options for prenatally determining risk of an unbalanced pregnancy. The MaterniT® GENOME test reports on genome-wide copy number variations >7Mb, making it uniquely positioned to detect deletions and duplications, such as those in unbalanced translocations. Since late 2015, more than 10,000 MaterniT® GENOME samples have been ordered. Here we describe three cases where unbalanced translocations have been detected or discovered. METHODS 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. 1 Sequencing data were analyzed using a novel algorithm to detect trisomies and sub chromosomal events, and genome wide events 7Mb and larger, as described by Leowitz et al. 2 CONCLUSIONS Approximately 1 in 500 individuals is a balanced translocation carrier 3 and has significant risk of offspring with unbalanced karyotypes. Unbalanced translocations are typically associated with fetal loss and abnormal phenotypes. Until the introduction of MaterniT® GENOME these families had limited prenatal screening options. MaterniT® GENOME has proven valuable for families with a known translocation and has also aided in detection of previously unknown familial translocations. MaterniT® GENOME is a relevant screening tool for families with a known translocation or suggestive family history, and as such would be an appropriate addition to the pre-test genetic counseling discussion. 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. Leowitz RB, Tynan J, Liu T, et al. Clinical validation of a non-invasive prenatal test for genome-wide detection of fetal copy number variants. American Journal of Obstetrics & Gynecology. doi: http://dx.doi.org/10.1016/j. ajog.2016.02.030 3. Hook EB, Hamerton JL. The frequency of chromosome abnormalities detected in consecutive newborn studies - differences between studies - results by sex and by severity of phenotypic involvement. in Hook EB, Porter LH (eds) Population Cytogenetics. New York: Academic Press, 1977, pp 66-79. SEQUENOM®, MaterniT® and Sequenom Laboratories™ are trademarks of Sequenom, Inc. 31-41541R1.0_0616 Indication: AMA; abnormal serum screening. MaterniT® GENOME result: 30Mb gain of chromosome 16(q21-q24.3) and 10.9Mb loss of chromosome 5(p15.33-p15.2) as displayed in the upper and lower ideogram, respectively. Result is suggestive of an unbalanced translocation. Amniocentesis confirmed 46,XX,+der(5),t(5;16), (p15.2;q21). A maternal balanced t(5;16) was subsequently revealed. Case 2 Case 1 Case 3 Test Result Positive Gain of chromosome 1 1 (q23.3-q25) material, Gain of chromosome 22(q11.1-q11.21) material Lab Director's Comments A gain of chromosome 1 1 material was observed. It is estimated to be 18.40Mb in size and is suggestive of a duplication in the region q23.3-q25. Also, a gain of chromosome 22 material was observed. It is estimated to be 3.00Mb in size and is suggestive of a duplication in the region q11.1-q11.21. These regions may contain one or more clinically significant genes. This may represent an unbalanced t(11:22). Family history of t(11;22) is noted. Genetic counseling and clinical correlation are recommended. Confirmatory testing is required if fetal confirmation and clinical interpretation of the suspected event are desired. Please refer to the "Performance" and "Limitations of the Test" sections of this laboratory report for additional information. Samantha Caldwell 2 *, Sidra Boshes 1 *, Jenna Wardrop 1 , Theresa Boomer 1 , Phillip Cacheris 1 , Hany Magharyous 1 , Ron McCullough 1 1 Sequenom Laboratories™, San Diego, CA ; 2 Sequenom Laboratories™, Morrisville, NC; *Co-first authorship

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