Cherchez la femme: maternal incidental findings can explain discordant prenatal cell-free DNA sequencing results

Abstract

Circulating DNA fragments in a pregnant woman's plasma derive from three sources: placenta, maternal bone marrow, and fetus. Prenatal sequencing to noninvasively screen for fetal chromosome abnormalities is performed on this mixed sample; results can therefore reflect the maternal as well as the fetoplacental DNA. Although it is recommended that pretest counseling include the possibility of detecting maternal genomic imbalance, this seldom occurs. Maternal abnormalities that can affect a prenatal screening test result include disorders that affect the size and metabolism of DNA, such as B12 deficiency, autoimmune disease, and intrahepatic cholestasis of pregnancy. Similarly, maternal tumors, both benign and malignant, can release DNA fragments that contain duplications or deletions. Bioinformatics algorithms can subsequently interpret the raw sequencing data incorrectly, resulting in false-positive test reports of fetal monosomies or test failures. Maternal sex-chromosome abnormalities, both constitutional and somatic, can generate results that are discordant with fetal ultrasound examination or karyotype. Maternal copy-number variants and mosaicism for autosomal aneuploidies can also skew interpretation. A maternal etiology should therefore be considered in the differential diagnosis of prenatal cell-free DNA test failures, false-positive and false-negative sequencing results. Further study is needed regarding the clinical utility of reporting maternal incidental findings.

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

“…Another major reason for a discordant cfDNA result is that the pregnant woman herself has a partial or mosaic autosomal or sex chromosome aneuploidy . Sex chromosome aneuploidies have a mild clinical phenotype and may be clinically unrecognized in the pregnant woman .…”

“…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.…”

The fragmentation patterns of maternal plasma cell‐free DNA and its applications in non‐invasive prenatal testing

“…12,62 The sensitivities and specificities for detection of the common aneuploidies in high-risk women were 97% and 99.7% for trisomy 21, 93% and 99.7% for trisomy 18, and 95% and 99.9% for trisomy 13, respectively. 8,13,62,63 False positive results attributed to cancer 64 and autoimmune diseases, 65 and false negative results attributed to low-fetal fraction 10 were reported in analysis of maternal plasma samples. 8 Fetal fraction can be low in early gestation before 8 weeks, 66 and other biological influences such as maternal autoimmune disease, 67,68 increasing maternal weight 56,66 and assisted reproductive technology conception, 69 parity and maternal age.…”

Fetal sex discordance between noninvasive prenatal screening results and sonography: A single institution's experience and review of the literature

“…As such, any NIPS result that is abnormal, ambiguous, or discrepant to fetal or postnatal phenotype requires further evaluation and diagnostic testing (ACOG, ; Bianchi, ; Byers et al, ; Richardson et al, ). The technology involved in NIPS is new and complex, and advanced methodologies leave numerous potentials for pitfalls.…”

“…This significant amount of maternal DNA may lead to confounding results in cases of any deviations in the maternal genome. Thus, NIPS is a screening test and should not be considered diagnostic (ACOG, 2015;Bianchi, 2018;Gregg, Gross, Best, et al, 2013).…”