Genomic characteristics of miscarriage copy number variants

Abstract

Studies of copy number variants (CNVs) in miscarriages are rare in comparison to post-natal cases with developmental abnormalities. The overall characteristics of miscarriage CNVs (size, gene content and function) are therefore largely unexplored. Our goal was to assess and compare the characteristics of CNVs identified in 101 euploid miscarriages from four high-resolution array studies that documented both common miscarriage CNVs (i.e. CNVs found in controls from the Database of Genomic Variants, DGV) and rare miscarriage CNVs (not reported in DGV). Our miscarriage analysis included 24 rare CNVs with 93 genes, and 372 common CNVs (merged into 119 common CNV regions; CNVRs) with 354 genes. The rare and common CNVs were comparable in size (median size of ∼ 0.16 and 0.14 Mb, respectively); however, rare CNVs showed a significantly higher gene density, with 56 genes/Mb in rare and 24 genes/Mb in common CNVs (P = 0.03). Rare CNVs also had two times more genes with mouse knock-out models which were reported for 42% of rare and 19% of common CNV genes. No specific pathway enrichment was noted for 24 rare CNV genes, but common CNV genes showed significant enrichment in genes from immune-response related pathways and pregnancy/reproduction-related biological processes. Our analysis of CNVs from euploid miscarriages suggests that both rare and common CNVs could have a role in miscarriage by impacting pregnancy-related genes or pathways. Cataloguing of all CNVs and detailed description of their characteristics (e.g. gene content, genomic breakpoints) is desirable in the future for better understanding of their relevance to pregnancy loss.

Keywords: CNV; bioinformatics; genomics; microarray; miscarriage.

Figure 1

Analysis of the function of CNV genes. Rare and common miscarriage CNV genes associated with embryonic lethality, pregnancy-associated abnormalities, and/or placental-specific expression were identified. This was determined by assessing the 39/93 rare miscarriage CNV genes and 67/354 common miscarriage CNV genes that had reported mammalian phenotypes in mouse knock-out studies, catalogued on MGI, as well as assessing all 93 rare and 354 common genes against human placental-specific genes listed on TiGER, and TiSGeD. For details of the CNVs in which these genes are involved refer to Supplementary Tables SV–SVII. The number and percentage of genes (highlighted) associated with each category is indicated inside and outside of the corresponding colour-coded circles, respectively.