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High resolution global chromosomal aberrations from spontaneous miscarriages revealed by low coverage whole genome sequencing

      Abstract

      Objective

      Chromosome aberrations are generally considered as one of the most substantial causative factors contributing to spontaneous miscarriages. Cytogenetic analyses like G-banded karyotype and chromosomal microarray analyses are often performed to further investigate the chromosome status of a miscarried fetus.

      Study design

      Here, we describe a novel method, AnnoCNV, to detect DNA copy number variations (CNVs) using low coverage whole genome sequencing (WGS). We investigated the overall frequency of chromosomal abnormalities in 149 miscarriage specimens using AnnoCNV.

      Results

      Among 149 fetal miscarriage samples, more than two fifths of them (42.95%, 64) carried at least one chromosomal abnormality, and a subset (40) was identified as autosomal trisomy which account for 26.84% of all samples. We have also developed a robust algorithm in AnnoCNV, which is able to differentiate specifically karyotype 69,XXY from sex chromosomal aneuploidy 45,X, and to identify 45,X/46,XX mosaicism. Lastly, across the whole genome AnnoCNV identifies CNVs, which are associated with both reported symptoms and unknown clinical conditions.

      Conclusion

      This cost-effective strategy reveals genome wide discovery of chromosome aberrations at higher resolution, which are consistent with parallel investigation conducted by SNP based assay.

      Abbreviations:

      CNV (copy number variation), WGS (whole genome sequencing), CMA (chromosomal microarray analysis), NGS (next-generation sequencing), NKD (normal-karyotype database), DGV (database of genomic variants), OMIM (Online Mendelian Inheritance in Man)

      Keywords

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