Noninvasive prenatal testing aids in detecting parental balanced translocation and highlights limitations of karyotyping

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Results PAtIeNt HIstORY Results Pregnancy History G8P3-0-4-3; Prior Trisomy 13 conceptus (low resolution blood chromosomes) High Risk Indication Advanced Maternal Age (38 years old) MaterniT21 Plus® Results Trisomy 13, Female Ultrasound Findings Micrognathia at 12w6d; Intrauterine fetal demise noted at 15w0d NIPT Trace Details 24.3Mb duplication of 13q31.2 and 27.85Mb deletion of 4q32.2 POC Karyotype 46,XX (low resolution, 450-500 band level) Parental Karyotype 46,XX,t (4;13)(q32;q31) (high resolution maternal karyotype) Noninvasive prenatal testing aids in detecting parental balanced translocation and highlights limitations of karyotyping 31-41504R1.0_0315 INtROductION Noninvasive prenatal testing (NIPT) has rapidly changed the screening practices for pregnant women at an increased risk of fetal aneuploidy. This technology provides high sensitivity and specificity for Trisomy 21, 18, and 13. Overrepresentation of a chromosome can be detected by an increased Z-score in comparison with a normal euploid genome. Here we describe a case involving a partial chromosome 13 duplication and a maternal balanced translocation that highlighted the limitations of suboptimal karyotype resolution. MetHOds Maternal plasma samples were subjected to DNA extraction and library preparation followed by massively parallel sequencing as described by Jensen, et al. 1 Sequencing data were analyzed using an algorithm to detect trisomies and other subchromosomal events as described by Chen et al. 2 dIscussION & cONclusIONs A routine call to alert the provider of a positive MaterniT21 Plus result quickly grew more complicated. During the initial discussion surrounding the trisomy 13 NIPT result, a relevant patient history was shared that included a prior trisomy 13 pregnancy and multiple miscarriages. This prompted review of NIPT genomic traces, which showed segmental duplication of chromosome 13q and concurrent deletion of 4q. Parental karyotypes were subsequently ordered to rule out balanced translocations. The patient miscarried shortly thereafter and POC studies were pursued. A maternal translocation between chromosomes 4 and 13 was identified on a high resolution karyotype. However, POC karyotype studies were reported as normal female and thus were discrepant with the NIPT results. The laboratory conducting the POC studies cautioned that the resolution of the POC chromosomes was low and thus they were unable to rule out the presence of a subtle translocation. They recommended a microarray, which was not pursued due to financial concerns. In addition to the translocated material visible on the NIPT genomic traces for chromosomes 4 and 13, a small maternal deletion spike precedes each segment at the translocation breakpoints. This is a recurring phenomenon seen in NIPT genomic traces with known or suspected translocations. The presumption is that these spikes represent minimal loss of genomic material at the breakpoints, perhaps as consequence of the initial break and/or the splicing mechanism involved in joining the two segments together. This case demonstrates the unique insight NIPT data can provide, especially in relation to compromised POC samples. Clinicians should be aware that standard karyotyping may not have sufficient resolution to detect subchromosomal events detectable by NIPT. Accurate clinical information provided to the laboratory may aid in additional interpretation. In these cases, microarray studies or high resolution karyotyping are the preferred methods for confirming a suspected abnormality. Julie Jesiolowski 1 , Thomas Monroe 1 , Courtney Fitch 2 , Jenna Wardrop 3 , Theresa Boomer 3 , Juan-Sebastian Saldivar 3 1 Sequenom Laboratories™, Morrisville, NC ; 2 Lehigh Valley Maternal Fetal Medicine, Allentown, PA, 3 Sequenom Laboratories™, San Diego, CA 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, Tynan J, Ehrich M, et al. Detection of fetal subchromosomal abnormalities by sequencing circulating cell-free DNA from maternal plasma. Clinchem. 2015;61(4):233312. doi:10.1373/clinchem.2014.23312. Epub 2015 Feb 20. Table 1. Patient History & Results Figure 1. Individual chromosome ideograms display a 27.85 Mb deletion observed on 4q32.2qter (top) and a 24.3 Mb duplication observed on 13q31.2qter (bottom). Both of these fetal events coincide with the maternal translocation breakpoints confirmed via high resolution karyotype. Gain Loss Chromosome 13 genomic location Gain Loss Chromosome 4 genomic location Maternal 'spike' at chromosomal break Maternal 'spike' at chromosomal break

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