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

Ondrej Pös,Marcel Kucharik,Jan Radvanszky,Zuzana Kubiritova,Frantisek Duris,Tomas Szemes,Jaroslav Budis

doi:10.3390/ijms20184403

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.

Highlights

Copy number variation (CNV) is a segment of DNA with length ≥1 kbp which is presented at a variable copy number in comparison to the reference genome
CNVs ranging from kbp to kbp with median size kbp
We are suggesting the additional utility of genomic data generated through routine non-invasive prenatal test (NIPT) screening based on low-coverage massively parallel whole-genome sequencing of total plasma DNA from pregnant women

Summary

Introduction

Copy number variation (CNV) is a segment of DNA with length ≥1 kbp which is presented at a variable copy number in comparison to the reference genome. CNVs are important cause of structural variations in the human genome [2]. Various methods for CNV detection have been developed, from the conventional cytogenetic analysis (e.g., G-banded karyotype) through microarray-based methods (e.g., comparative genomic hybridization) to next-generation sequencing (NGS) [5]. Genomic microarrays provide a genome-wide coverage at a much higher resolution than a conventional cytogenetic analysis. This is the reason why microarray-based methods have been standard for CNV detection [6,7].

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