WisecondorFF: Improved Fetal Aneuploidy Detection from Shallow WGS through Fragment Length Analysis.

Tom Mokveld,Zaid Al-Ars,Marcel Reinders,Erik A Sistermans

doi:10.3390/diagnostics12010059

Tom Mokveld, Zaid Al-Ars + Show 2 more

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https://doi.org/10.3390/diagnostics12010059

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Abstract

In prenatal diagnostics, NIPT screening utilizing read coverage-based profiles obtained from shallow WGS data is routinely used to detect fetal CNVs. From this same data, fragment size distributions of fetal and maternal DNA fragments can be derived, which are known to be different, and often used to infer fetal fractions. We argue that the fragment size has the potential to aid in the detection of CNVs. By integrating, in parallel, fragment size and read coverage in a within-sample normalization approach, it is possible to construct a reference set encompassing both data types. This reference then allows the detection of CNVs within queried samples, utilizing both data sources. We present a new methodology, WisecondorFF, which improves sensitivity, while maintaining specificity, relative to existing approaches. WisecondorFF increases robustness of detected CNVs, and can reliably detect even at lower fetal fractions (<2%).

Highlights

IntroductionPrenatal screening is routinely used to verify and measure the health of the fetus, including the detection of chromosomal CNVs (copy number variations), in a timely manner [1]
Prenatal screening is routinely used to verify and measure the health of the fetus, including the detection of chromosomal CNVs, in a timely manner [1]
We introduce WisecondorFF, a methodology that detects chromosomal in the fetus from cfDNA that combines estimates based on read coverage as well as fragment size statistics

Summary

Introduction

Prenatal screening is routinely used to verify and measure the health of the fetus, including the detection of chromosomal CNVs (copy number variations), in a timely manner [1]. The noninvasive methods assess fetal health through indirect means such as through morphological properties using ultrasound scans [6,7], or biochemical markers by sampling the maternal serum [8,9]. Such screening methods must be performed at specific stages of the pregnancy [10], and are typically deployed in parallel [5,6], broadening the scope of detectable pathologies [10,11,12]

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