Identification of Structural Variation from NGS-Based Non-Invasive Prenatal Testing

Abstract

Copy number variants (CNVs) are an important type of human genome variation, which play a significant role in evolution contribute to population diversity and human genetic diseases. In recent years, next generation sequencing has become a valuable tool for clinical diagnostics and to provide sensitive and accurate approaches for detecting CNVs. In our previous work, we described a non-invasive prenatal test (NIPT) based on low-coverage massively parallel whole-genome sequencing of total plasma DNA for detection of CNV aberrations ≥600 kbp. We reanalyzed NIPT genomic data from 5018 patients to evaluate CNV aberrations in the Slovak population. Our analysis of autosomal chromosomes identified 225 maternal CNVs (47 deletions; 178 duplications) ranging from 600 to 7820 kbp. According to the ClinVar database, 137 CNVs (60.89%) were fully overlapping with previously annotated variants, 66 CNVs (29.33%) were in partial overlap, and 22 CNVs (9.78%) did not overlap with any previously described variant. Identified variants were further classified with the AnnotSV method. In summary, we identified 129 likely benign variants, 13 variants of uncertain significance, and 83 likely pathogenic variants. In this study, we use NIPT as a valuable source of population specific data. Our results suggest the utility of genomic data from commercial CNV analysis test as background for a population study.

Validation of Copy Number Variants Detection from Pregnant Plasma Using Low-Pass Whole-Genome Sequencing in Noninvasive Prenatal Testing-Like Settings

“…The recently published data from NIPT screening showed that 4.2% of individuals in the Central European region carry a CNV ≥ 600 kilobases (kb) [ 4 ], suggesting a higher frequency than commonly reported. A study by Ke et al on 14,235 NIPT cases found an incidence rate of CNVs in the general pregnant population of 1.69%.…”

Automated prediction of the clinical impact of structural copy number variations

“…CNV analysis is increasingly used in clinical testing through genome, exome, or gene panel sequencing. These methods have enabled genome-wide detection of CNVs in clinically affected individuals, as well as in the general population [12,13] . Due to a significant progress in the detection of structural variants, we are now able to detect thousands of structural variants with a deep coverage sequencing in a human genome.…”

Privacy preserving storage of sequenced genomic data

“…Moreover, current variant calling algorithms are not mature, and it is unknown which type of data produced by the sequencing process will be necessary for future algorithms [9] . Additionally, aligned reads can be employed directly in the detection of structural variations such as copy number variations (CNVs) or aneuploidies in clinical non-invasive prenatal testing (NIPT) [10][11][12] . These detection methods are not dependent on short variant analyses, since they use coverage data, determined by read alignment only.…”