33N Clinical relevance of screening for rare autosomal : a case of maternal J. Rafalko, MS, LCGC1, J. Helgeson, MS, CGC1, R. Sullenberger, MS, CGC2, C. Macedonia, MD2, T. Boomer, MS, CGC3, Sue Beruti, MD, MHA3 1. Sequenom, Inc., San Diego, CA, 2. Lancaster General Health, Maternal Fetal Medicine, Lancaster, PA, 3. Sequenom Laboratories, San Diego, CA

I. Introduction Traditionally, fetal screening has focused on autosomal of 21, 18, and 13. Subsequently, cell-free DNA (cfDNA) screening has expanded to include sex aneuploidies, select microdeletions, and recently genome-wide analysis. Though uncommon after the first trimester, aneuploidy of any can occur in placental and fetal tissues. Some autosomal aneuploidies present at conception are rescued and restored to a euploid state. When this occurs with imprinted chromosomes, it can lead to a euploid fetus with a genetic syndrome due to uniparental disomy (UPD). Figure 2: Genome-wide profile from cfDNA sequencing showing overrepresentation of

Genetic Etiology Proportion of PWS II. Methods Interstitial of 15q11.2-q13 65-75% An approximate 79.55Mb gain of chromosome 15 material was observed, suggestive of 15. Maternal blood samples submitted to Sequenom Laboratories® for MaterniT® Maternal uniparental disomy (UPD) 20-30%

GENOME testing were subjected to DNA extraction, library preparation, and Figure 1: MaterniT® GENOME report including detailed laboratory director comments and ideogram Imprinting defect 1-3% whole-genome massively parallel sequencing as described by Jensen et al.1

Sequencing data were analyzed using a novel algorithm to detect aneuploidies Table 1: Frequency of genetic mechanisms resulting in PWS3 and other subchromosomal events as described by Lefkowitz et al.2 IV. Conclusion III. Results This case illustrates the clinical relevance of screening for esoteric trisomies with cfDNA. Though the fetus did not have trisomy 15, the cfDNA test identified a trisomy in the A 42 year old patient elected genome-wide cfDNA screening after genetic counsel- placenta, presumably rescued in fetal tissue, which led to maternal UPD of chromosome ing. Screening was positive, indicating an increased representation of chromosome 15 and a fetal diagnosis of Prader-Willi syndrome. Diagnosing Prader-Willi syndrome 15, consistent with trisomy 15. The trisomy was predicted to be present at Maternal Paternal prenatally allows patients to make reproductive decisions, including pregnancy termina- 35% mosaicism. The patient elected to pursue amniocentesis which returned a tion, adoption, and preparing for a child with disabilities. normal fetal karyotype, 46,XX. Subsequent testing of amniocytes detected mater- nal isodisomy of chromosome 15. Maternal UPD15 is a cause of Prader-Willi syndrome. V. 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. Biparental inheritance UPD UPD UPD UPD (normal) Maternal Maternal Paternal Paternal 2. Lefkowitz RB, Tynan JA, Liu T, et al. Clinical validation of a noninvasive prenatal test for genomewide detection of fetal copy heterodisomy isodisomy heterodisomy isodisomy number variants. Am J Obstet Gynecol 2016;215:227.e1-16. 3. Adapted from: Driscoll DJ, Miller JL, Schwartz S, et al. Prader-Willi Syndrome. 1998 Oct 6 [Updated 2016 Feb 4]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1330/ ©2017 Laboratory Corporation of America® Holdings All rights reserved. Figure 3: Biparental vs. uniparental inheritance and pictorial representation of various types of UPD