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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.

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BackgroundChromosomal abnormalities are a frequent cause of miscarriage; however the aetiology of karyotypically normal miscarriages remains unknown in many cases.ObjectiveOur objective was to find new genetic causes of idiopathic miscarriages by evaluating miscarriage CNVs and sequence variants detected by whole exome sequencing (WES).MethodsWe used a) bioinformatics to assess genomic characteristics of CNVs (size, gene content) reported in 4 recent studies of 101 miscarriages; b) RNA and protein expression to determine the function of their integral genes in miscarriage cells and c) exome sequencing to look for mutations associated with recurrent pregnancy loss.ResultsThe rare and common CNVs reported in 101 miscarriages were comparable in size (median size of ˜0.18 and 0.14 Mb, respectively), however, rare CNVs showed a trend towards higher gene density with 46 genes/Mb in rare and 21 genes/Mb in common CNVs (p = 0.06). For 3/14 genes integral to CNVs the RNA and protein expression was abnormal in miscarriages. These genes have a role in processes required for successful pregnancy development: TIMP2 and TRAPPC2 in tissue remodelling, cell adhesion and migration and OFD1 in cilia function. WES of recurrent miscarriages from 4 couples revealed 11 genes with rare and pathogenic compound heterozygous variants. It is of interest that 4/11 variants occurred in dynein genes, known to be involved in cilia function, and required for early organogenesis. Compound heterozygous mutations in one of these genes, DYNC2H1, were recently reported in a family with recurrent fetal loss.ConclusionOur study represents a comprehensive assessment of genomic changes in miscarriage and has the potential to identify novel genetic causes of pregnancy loss.asta.

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