Background Chromosomal abnormalities are a frequent cause of miscarriage; however the aetiology of karyotypically normal miscarriages remains unknown in many cases.

Objective Our objective was to find new genetic causes of idiopathic miscarriages by evaluating miscarriage CNVs and sequence variants detected by whole exome sequencing (WES).

Methods We 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.

Results The 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.

Conclusion Our study represents a comprehensive assessment of genomic changes in miscarriage and has the potential to identify novel genetic causes of pregnancy loss.asta.