The impact of maternal plasma DNA fetal fraction on next generation sequencing tests for common fetal aneuploidies

TLDR

Maternal plasma contains cell‑free DNA from both mother and placenta, and the proportion from placenta—called fetal fraction—averages 10–15 % between 10–20 weeks but can vary widely; higher fetal fraction improves next‑generation sequencing screening, while values below 3–4 % render samples unsuitable. The authors examine how fetal fraction influences next‑generation sequencing for common fetal aneuploidies, aiming to clarify its strengths and limitations. They find that higher fetal fraction improves Down syndrome test result distribution, that maternal weight is the strongest predictor of low fetal fraction and false negatives, and that mosaicism reduces effective fetal fraction, thereby affecting test performance.

Abstract

Maternal plasma contains circulating cell-free DNA fragments originating from both the mother and the placenta. The proportion derived from the placenta is known as the fetal fraction. When measured between 10 and 20 gestational weeks, the average fetal fraction in the maternal plasma is 10% to 15% but can range from under 3% to over 30%. Screening performance using next-generation sequencing of circulating cell-free DNA is better with increasing fetal fraction and, generally, samples whose values are less than 3% or 4% are unsuitable. Three examples of the clinical impact of fetal fraction are discussed. First, the distribution of test results for Down syndrome pregnancies improves as fetal fraction increases, and this can be exploited in reporting patient results. Second, the strongest factor associated with fetal fraction is maternal weight; the false negative rate and rate of low fetal fractions are highest for women with high maternal weights. Third, in a mosaic, the degree of mosaicism will impact the performance of the test because it will reduce the effective fetal fraction. By understanding these aspects of the role of fetal fraction in maternal plasma DNA testing for aneuploidy, we can better appreciate the power and the limitations of this impressive new methodology.