Maternal mosaicism for a large segmental duplication of 18q as a secondary finding following non‐invasive prenatal testing and implications for test accuracy

Abstract

Non-invasive prenatal testing (NIPT) for fetal aneuploidies by massively parallel sequencing has transformed the approach to prenatal care. The presence of circulating fetal cell-free DNA (cfDNA) in maternal plasma, which is derived primarily from the placenta, is the basis of this test.1 Studies comparing NIPT to serum or combined screening have shown that NIPT outperforms these screening options in trisomy detection and has significantly lower false positive rates. 2-4 Biological causes of false positive NIPT results may include maternal mosaicism (primarily sex chromosome mosaicism), confined placental mosaicism, co-twin demise, maternal malignancy and maternal copy number variation. 2,5 Here, we present a case of a nonstandard NIPT result involving a large and pathogenic partial duplication of chromosome 18q first indicated by NIPT. Subsequent prenatal diagnosis confirmed the presence of the duplication in the fetus, which was inherited from the phenotypically normal mother who carried the same chromosomal imbalance, but in mosaic form. A review of the NIPT data indicates that maternal mosaicism for this large segmental imbalance is sufficient to cause a false positive NIPT result in subsequent pregnancies, in the absence of the imbalance being transmitted to the fetus. Therefore, maternal mosaicism for large segmental copy number abnormalities may be yet another rare cause of false positive NIPT results, which further highlights the need for confirmatory invasive testing whenever an abnormal NIPT result is returned.The patient was a 38-year-old G3P2 woman who underwent first trimester combined screening. Risks for trisomy 18 and trisomy 21 were calculated at 1:13,100 and 1:1,690, respectively. No further investigations for Down syndrome or trisomy 18 were recommended on the basis of these low risk results. A fetal anomaly ultrasound scan at 20 weeks of gestation identified an isolated aberrant right subclavian artery. The sonologist counselled a low risk for chromosome abnormality 6 but informed the patient of the option of NIPT and amniocentesis. The patient was not referred for formal genetic counselling and pursued NIPT independently.Maternal venous blood was collected for NIPT at 20 + 6 weeks of gestation, and testing was performed by Natera Panorama ™ test, which is a targeted, multiplexed, single nucleotide polymorphism (SNP)-based NIPT assay. 7 The NIPT returned an unexpected finding with no result for chromosome 18 because of an 'atypical finding outside the current scope of the test'. The atypical finding was a suspicion of a partial duplication of chromosome 18. To help direct follow-up testing, a request was made for genomic or cytogenetic breakpoint information but was declined on the basis that the information being sought was outside the current scope of the test. Genetic counselling was arranged, and the patient elected amniocentesis at 22 weeks of gestation, at which time a small ventricular septal defect on ultrasound was also noted. As no positional information for the suspected duplication...

Follow-up of multiple aneuploidies and single monosomies detected by noninvasive prenatal testing: implications for management and counseling

“…For the 42 discordant cases with normal fetal karyotypes and no reported maternal disease, the NIPT result might reflect CPM, residual cfDNA from an unrecognized vanished twin, or a maternal copy number variant . Grati et al .…”

“…For the 42 discordant cases with normal fetal karyotypes and no reported maternal disease, the NIPT result might reflect CPM, 19 residual cfDNA from an unrecognized vanished twin, 20 or a maternal copy number variant. 21,22 Grati et al determined the potential contribution of CPM to the NIPT false-positive rate, demonstrating that chromosomes 13 and X were more likely to be associated with CPM than chromosomes 18 and 21. 23 There was one suspected case of CPM in our dataset, a partially concordant case that had postnatal placental analysis.…”

Biological explanations for discordant noninvasive prenatal test results: Preliminary data and lessons learned

“…35 More recently, it has become appreciated that both small maternal duplications (CNVs) and larger mosaic maternal duplications can cause false-positive cfDNA results for autosomal aneuploidy. 44,46,47 Other maternal conditions, such as a prior solid organ transplant from a male donor, 48 have been shown to be the etiology for discordant sex chromosome cfDNA results. Subclinical organ rejection results in the release of cfDNA into the plasma.…”

Contribution of maternal copy number variations to false‐positive fetal trisomies detected by noninvasive prenatal testing

“…Follow‐up case studies of false‐positive NIPT results has identified a variety of potential causes including a vanishing twin, unidentified maternal tumors, maternal mosaicism, and confined placental mosaicism . More recently, several groups using different NIPT methodologies have reported maternal copy number variations (CNVs) as an additional cause of false‐positive NIPT results . In order to further investigate the potential contribution of maternal CNVs to false‐positive NIPT results, we performed NIPT on a large cohort of 112 021 pregnant women using low coverage massively parallel sequencing and analyzed the 74 false‐positive trisomy samples for the presence of maternal CNVs.…”

“…[14][15][16][17][18][19][20] More recently, several groups using different NIPT methodologies have reported maternal copy number variations (CNVs) as an additional cause of false-positive NIPT results. 6,[21][22][23][24][25][26] In order to further investigate the potential contribution of maternal CNVs to false-positive NIPT results, we performed NIPT on a large cohort of 112 021 pregnant women using low coverage massively parallel sequencing and analyzed the 74 falsepositive trisomy samples for the presence of maternal CNVs.…”