In our previous work, genomic data generated through non-invasive prenatal testing (NIPT) based on low-coverage massively parallel whole-genome sequencing of total plasma DNA of pregnant women in Slovakia was described as a valuable source of population specific data. In the present study, these data were used to determine the population allele frequency of common risk variants located in genes associated with colorectal cancer (CRC) and Lynch syndrome (LS). Allele frequencies of identified variants were compared with six world populations to detect significant differences between populations. Finally, variants were interpreted, functional consequences were searched for and clinical significance of variants was investigated using publicly available databases. Although the present study did not identify any pathogenic variants associated with CRC or LS in the Slovak population using NIPT data, significant differences were observed in the allelic frequency of risk CRC variants previously reported in genome-wide association studies and common variants located in genes associated with LS. As Slovakia is one of the leading countries with the highest incidence of CRC among male patients in the world, there is a need for studies dedicated to investigating the cause of such a high incidence of CRC in Slovakia. The present study also assumed that extensive cross-country data aggregation of NIPT results would represent an unprecedented source of information concerning human genome variation in cancer research.
Objective: Discovery of fetal cell-free DNA fragments in maternal blood revolutionized prenatal diagnostics. Although non-invasive prenatal testing (NIPT) is already a matured screening test with high specificity and sensitivity, the accurate estimation of the proportion of fetal fragments, called fetal fraction, is crucial to avoid false-negative results. Methods: We collected 6999 samples from women undergoing NIPT testing with a single male fetus to demonstrate the influence of fetal fraction by the maternal and fetal characteristics. Results: We show several fetal fraction discrepancies that contradict the generally presented conventional view. At first, the fetal fraction is not consistently rising with the maturity of the fetus due to a drop in 15 weeks of maturation. Secondly, the male samples have a lower fetal fraction than female fetuses, arguably due to the smaller gonosomal chromosomes. Finally, we discuss not only the possible reasons why this inconsistency exists but we also outline why these differences have not yet been identified and published. Conclusion: We demonstrate two non-intuitive trends to better comprehend the fetal fraction development and more precise selection of patients with sufficient fetal fraction for accurate testing.
Background COVID-19 caused by the SARS-CoV-2 infection may result in various disease symptoms and severity, ranging from asymptomatic, through mildly symptomatic, up to very severe and even fatal cases. Although environmental, clinical, and social factors play important roles in both susceptibility to the SARS-CoV-2 infection and progress of COVID-19 disease, it is becoming evident that both pathogen and host genetic factors are important too. In this study, we report findings from whole-exome sequencing (WES) of 27 individuals who died due to COVID-19, especially focusing on frequencies of DNA variants in genes previously associated with the SARS-CoV-2 infection and the severity of COVID-19. Results We selected the risk DNA variants/alleles or target genes using four different approaches: 1) aggregated GWAS results from the GWAS Catalog; 2) selected publications from PubMed; 3) the aggregated results of the Host Genetics Initiative database; and 4) a commercial DNA variant annotation/interpretation tool providing its own knowledgebase. We divided these variants/genes into those reported to influence the susceptibility to the SARS-CoV-2 infection and those influencing the severity of COVID-19. Based on the above, we compared the frequencies of alleles found in the fatal COVID-19 cases to the frequencies identified in two population control datasets (non-Finnish European population from the gnomAD database and genomic frequencies specific for the Slovak population from our own database). When compared to both control population datasets, our analyses indicated a trend of higher frequencies of severe COVID-19 associated risk alleles among fatal COVID-19 cases. This trend reached statistical significance specifically when using the HGI-derived variant list. We also analysed other approaches to WES data evaluation, demonstrating its utility as well as limitations. Conclusions Although our results proved the likely involvement of host genetic factors pointed out by previous studies looking into severity of COVID-19 disease, careful considerations of the molecular-testing strategies and the evaluated genomic positions may have a strong impact on the utility of genomic testing.
Background: COVID-19 caused by SARS-CoV-2 infection may result in various disease symptoms and severity, ranging from asymptomatic, through mild, up to very severe and fatal cases. Although environmental, clinical, and social factors play important roles in both susceptibility to SARS-CoV-2 infection and COVID-19 disease progress, it is becoming evident that both pathogen and host genetic factors are important too. Here we report whole-exome sequencing (WES) findings of 27 individuals who died as a result of COVID-19 infection, especially focusing on frequencies of DNA variants in genes previously associated with SARS-CoV-2 infection and COVID-19 severity. Results: We selected risk DNA variants/alleles or target genes using four different approaches: 1) aggregated GWAS results from the GWAS Catalog; 2) selected publications from PubMed; 3) the aggregated results of the Host Genetics Initiative database; and 4) a commercial DNA variant annotation/interpretation tool providing its own knowledgebase. We divided these variants/genes into those reported to influence the susceptibility to SARS-CoV-2 infection and those influencing COVID-19 severity. Based on these, we compared frequencies of alleles among the fatal COVID-19 cases to frequencies identified in two population control datasets (non-Finnish European population from the gnomAD database and genomic frequencies specific for the Slovak population from our own database). Our comparisons delineated a trend of higher frequencies of severe COVID-19 associated risk alleles among fatal COVID-19 cases, when compared to both control population datasets. This trend reached statistical significance specifically when using the HGI derived variant list. We also analyzed other approaches to WES data evaluation, where we showed their usage as well as limitations. Conclusions: Although our results proved the likely involvement of host genetic factors pinned out by previous studies for COVID-19 disease severity, careful considerations about the molecular-testing strategies and the evaluated genomic positions may have a strong impact on the utility of genomic testing.
PURPOSE: In our previous work, we described genomic data generated through non-invasive prenatal testing (NIPT) based on low-coverage massively parallel whole-genome sequencing of total plasma DNA of pregnant women in Slovakia as a valuable source of population specific data. In the present study, we used these data to determine the population allele frequency of common risk variants located in genes associated with colorectal cancer (CRC) and Lynch syndrome (LS). METHODS: Allele frequencies of identified variants were compared with six world populations to detect significant differences between populations. Finally, we interpreted variants and searched for functional consequences and clinical significance of variants using publicly available databases.RESULTS: Although we could not identify any pathogenic variants associated with CRC or LS in the Slovak population using NIPT data, we observed significant differences in the allelic frequency of risk CRC variants previously reported in GWAS and common variants located in genes associated with LS. CONCLUSION: As Slovakia is the third country with the highest incidence of CRC per 100 000 population in the world, we highlight a need for studies dedicated to the cause of such a high incidence of CRC in Slovakia. We also assume that extensive cross-country data aggregation of NIPT results would represent an unprecedented source of information about human genome variation, also in cancer research.
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