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A selection of 2017 articles foreshadowing future clinical WGS applications

We usually focus on current clinical applications of whole genome sequencing (WGS), but we’re just as interested in seeing how the technology is advancing for future clinical use.

In a twist on typical “best of” year-in-review posts, we’re taking time in this first week of 2018 to highlight a few 2017 scientific publications that provided a glimpse into possible clinical WGS applications in the future. Some have a longer and more uncertain path to clinical use than others, but we saw interesting potential in the technology and analyses described in the following selected articles.

Expanding prenatal screening to include rare autosomal trisomies

WGS of circulating cell-free DNA (cfDNA) in maternal plasma is frequently used for prenatal screening for common trisomies, but is usually limited to chromosomes 21, 18, 13, X and Y. In the August issue of Science Translational Medicine, Pertile et al1 hypothesized that systematic evaluation of WGS data from all chromosomes could be used to identify additional rare trisomies, enabling a more complete pregnancy picture. For their study, the authors analyzed nearly 400 previously screened cases that were flagged as having higher than expected levels of background noise when assessing the status of targeted chromosomes. The elevated background noise indicated a higher or lower than expected density count over non-test chromosomes and the potential for undetected aneuploidy events. Visual review of these cases identified a high percentage of rare autosomal trisomies (RATs), with the most common occurrence for chromosomes 7, 15, 16 and 22. Available clinical outcome data linked many of these detected RAT cases to miscarriage, fetal mosaicism and confirmed or suspected uniparental disomy, lending support to the author’s theory that analysis of aneuploidies in all chromosomes could help identify additional at-risk pregnancies.

Comprehensive non-invasive prenatal testing for genetic disorders

Cases of WES and WGS being used for diagnosis of rare genetic disorders in newborns, children and older patients are regularly described in published literature. In a new variation on this theme, Chen et al2 described, in the December issue of Prenatal Diagnostics, a procedure to identify, isolate and analyze circulating fetal cells (CFCs) from maternal whole blood. They combined a double negative selection process with genetic identification to manually isolate single CFCs. Single cell whole genome amplification was followed by low coverage genome sequencing to evaluate DNA quality and deep coverage genome sequencing to extract data for variant analysis. Detection of disease-associated variants that were later confirmed by sequencing unamplified genomic DNA demonstrated the potential of the procedure to be adapted for comprehensive non-invasive prenatal testing of genetic disorders using CFCs isolated from maternal blood.

Pre-emptive pharmacogenetic screening

As discussed above, WGS has been shown to be valuable in diagnosing genetic disorders. In the May issue of Genomic Medicine, Cohn et al3 explored whether the same data may be used to provide personalized information about the safety and effectiveness of medication. Using data from a cohort of 98 children who had previously received WGS for diagnostic purposes, the authors analyzed single nucleotide and indel variants in 19 genes with known pharmacogenetic effects as well as CYP2D6 copy number, comparing their results against traditional genotyping methods. While complete concordance was not observed, particularly for CYP2D6*4 haplotypes, the results of the study suggest that WGS can be used for pre-emptive pharmacogenetic screening. With reflex targeted genotyping used to supplement WGS analysis for pharmacologically important genes with lower concordance.

Facilitating diagnosis of heterogeneous disorders through genetic clustering of ethnically similar individuals

Published in the March issue of Scientific Reports, Yu et al4 described a novel strategy for comparing an individual’s genomic signature to that of others within their ethnic group as a way to facilitate diagnosis of genetically heterogeneous, prevalent disorders. To test their strategy they used WGS, which enabled detection of many more mutations than traditional genotyping. After obtaining the DNA sequence of patients diagnosed with major depressive disorder (MDD) and ethnically-matched controls, they analyzed the data to calculate the distance matrix between each participant for each chromosome, then analyzed the distance matrices to cluster the participants. While the statistical distribution of single nucleotide variants across each chromosome was similar between the depression and control groups, the depression patients and control subjects distinctly segregated to separate clusters. Giving rise to the possibility that an individual’s genomic signature could be tested for whether it clusters with a particular group of patients, providing information about predisposition or aiding in diagnosis.


1. Pertile et al. Rare autosomal trisomies, revealed by maternal plasma DNA sequencing, suggest increased risk of feto-placental disease. Sci Transl Med. 2017 Aug 30;9(405). PubMed ID 28855395

2. Chen et al. Isolation and whole genome sequencing of fetal cells from maternal blood towards the ultimate non-invasive prenatal testing. Prenat Diagn. 2017 Dec;37(13):1311-1321. PubMed ID 29144536

3. Cohn et al. Genome sequencing as a platform for pharmacogenetic genotyping: a pediatric cohort study. NPJ Genom Med. 2017 May 26;2:19. PubMed ID 29263831

4. Yu et al. A novel strategy for clustering major depression individuals using whole-genome sequencing variant data. Sci Rep. 2017 Mar 13;7:44389. PubMed ID 28287625

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