Detection of Fetal Copy Number Aberrations by Shallow Sequencing of Maternal Blood Samples

Motivation: Numerous genetic disorders can be detected in prenatal diagnosis using Chorionic Villus Sampling. As this brings a 1:100 chance for miscarriage, this method is only applied when the fetus is suspected to have an increased chance at having an aberration. It is known that a small percentage of DNA in maternal plasma is of fetal origin and with the upswing of Next Generation Sequencing (NGS) it is now possible to diagnose trisomy 21 cases non-invasively using maternal blood samples. Other and smaller aberrations can be detected with this kind of blood samples using high coverage NGS, but this makes these methods more expensive. Our goal was to find a method to detect small aberrations using only shallow sequencing (low coverage NGS), keeping the costs per sample to a minimum. Methods: We developed an approach (called WISECONDOR) that determines whether a small region is aberrated by looking whether the read count within that region differs abnormally compared to the read counts of other similarly behaving regions within the same test sample. The other similarly behaving regions are considered to have similar NGS biases, such as GC-richness, and are found by comparing read count correlations over a set of healthy samples. Results: The developed script was able to correctly identify all tested T13, T18 and T21 cases. Aberrations such as del(13)(q12.3q14.3), i(12p10) and i(18q10) were also correctly called. The amount of false positives was minimal and even zero when the size of the aberrations was at least 20Mb, while the test samples varied from only 0.15 to 1.66 fold coverage. This shows that most fetal fetal copy number aberrations can be detected by shallow sequencing of maternal blood samples.Computer Science, MKE, Track BioinformaticsPattern Recognition & BioinformaticsElectrical Engineering, Mathematics and Computer Scienc