Cell-free DNA (cfDNA)-based noninvasive prenatal testing (NIPT) became clinically available in 2012 to screen for common aneuploidies, including trisomies 13, 18, and 21. Test menus have since expanded to include additional options, such as sex chromosome analysis and select microdeletion syndromes. Although most patients receive a negative or positive result for one of the common aneuploidies, some patients receive unusual findings, such as an autosomal monosomy or multiple aneuploidies. True multiple aneuploidies are rare and generally unlikely to result in a clinically recognized pregnancy or viable birth.1-3 Several recent reports have linked NIPT results of multiple aneuploidies and autosomal monosomy to occult maternal tumors, either benign or malignant status.4-8 This has generated interest from providers; however, there was limited data to guide appropriate patient counseling following an atypical NIPT result.
A recently published study9 sought to review all multiple aneuploidy and autosomal monosomy results reported through the Illumina CAP-accredited and CLIA-certified clinical lab in Redwood City, CA. Analysis of just over 110,000 cases revealed 138 (0.12%) cases reported as a multiple aneuploidy or autosomal monosomy (Figure 1, click to enlarge). These rare results were categorized into three groups: single autosomal monosomy (n=65), single trisomy with a sex chromosome abnormality (n=35) and multiple aneuploidies (n=37). Outcome information was available for 79 (57%) cases in this study cohort (Figure 2, click to enlarge).
Within the 79 cases with outcomes, full or partial concordance was confirmed in 16 cases (20.3%). Other biological etiologies were confirmed for an additional 11 cases (13.9%), including six cases of maternal malignancy and five cases of a fetal or maternal chromosome abnormality in a non-test (reference) chromosome. Adding analysis of whole genome evaluation of all 24 chromosomes to the test menu might help alleviate the ambiguity currently associated with unusual NIPT results. This study showed that partial or full discordance may still be seen secondary to other biological etiologies.
The strength of this study is that it provides a resource for providers counseling patients with unusual NIPT results. Despite the small cohort size, outcomes include several possible explanations for atypical NIPT results that providers may consider when addressing the potential underlying explanations for each patient’s unique test result. This study reminds patients and providers that NIPT is a screening tool and as recommended by several societies, confirmatory testing should be offered to all women with an abnormal NIPT result.10-13
Kovaleva NV, Mutton DE. Epidemiology of double aneuploidies involving chromosome 21 and the sex chromosomes. Am J Med Genet A 2005;134A(1):24-32.
Reddy KS. Double trisomy in spontaneous abortions. Hum Genet 1997;101(3):339-45.
Subramaniyam S, Pulijaal VR, Mathew S. Double and multiple chromosomal aneuploidies in spontaneous abortions: A single institutional experience. J Hum Reprod Sci 2014;7(4):262-8.
Bianchi DW, Chudova D, Sehnert AJ, et al. Noninvasive prenatal testing and incidental detection of occult maternal malignancies. JAMA. 2015;314(2):162-169.
Osborne CM, Hardisty E, Devers P, et al. Discordant noninvasive prenatal testing results in a patient subsequently diagnosed with metastatic disease. Prenat Diagn 2013;33(6):609-11.
McCullough RM, Almasri EA, Guan X, et al. Non-invasive prenatal chromosomal aneuploidy testing--clinical experience: 100,000 clinical samples. PLoS One 2014;9(10):e109173.
Amant F, Verheecke M, Wlodarska I, et al. Presymptomatic identification of cancers in pregnant women during noninvasive prenatal testing. JAMA Oncology 2015;1(6):814-9.
Snyder HL, Curnow KJ, Bhatt S, Bianchi DW. Follow-up of multiple aneuploidies and single monosomies detected by noninvasive prenatal testing: Implications for management and counseling. Prenat Diag. 2016 March; 36(3):201-209.
Dharajiya NG, Namba A, Horiuchi I, et al. Uterine leiomyoma confounding a noninvasive prenatal test result. Prenat Diagn 2015;35(10):990-3.
Gregg AR, Gross SJ, Best RG, et al. ACMG statement on noninvasive prenatal screening for fetal aneuploidy. Genet Med 2013;15(5):395-8.
Devers PL, Cronister A, Ormond KE, et al. Noninvasive prenatal testing/noninvasive prenatal diagnosis: the position of the National Society of Genetic Counselors. Journal of genetic counseling 2013;22(3):291-5.
ACOG, SMFM. Practice Bulletin 163: Screening for fetal aneuploidies. Committee for Practice Bulletins. 2016
Benn P, Borrell A, Chiu RW, et al. Position statement from the Chromosome Abnormality
Screening Committee on behalf of the Board of the International Society for Prenatal Diagnosis. Prenat Diagn 2015.
Images from Snyder HL, Curnow KJ, Bhatt S, Bianchi DW. Follow-up of multiple aneuploidies and single monosomies detected by noninvasive prenatal testing: Implications for management and counseling. Prenat Diagn. 2016;doi:10.1002/pd.4778.