1 The Faculty of Medicine, Aalborg University, VBN2 Aalborg University Hospital, The Faculty of Medicine, Aalborg University, VBN3 Klinik Kvinde-Barn og Urinvejskirurgi, The Faculty of Medicine, Aalborg University, VBN4 Gynækologi, Graviditet og Fødsel (Gynækologi og Obstetrik), The Faculty of Medicine, Aalborg University, VBN5 Klinik Diagnostik, The Faculty of Medicine, Aalborg University, VBN6 Klinisk Immunologi, The Faculty of Medicine, Aalborg University, VBN7 Human Molecular Genetics Research Group, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.8 unknown9 Department of Clinical Medicine, The Faculty of Medicine, Aalborg University, VBN
Recurrent miscarriage (RM) is a multifactorial disorder with acknowledged genetic heritability that affects ∼3% of couples aiming at childbirth. As copy number variants (CNVs) have been shown to contribute to reproductive disease susceptibility, we aimed to describe genome-wide profile of CNVs and identify common rearrangements modulating risk to RM. Genome-wide screening of Estonian RM patients and fertile controls identified excessive cumulative burden of CNVs (5.4 and 6.1 Mb per genome) in two RM cases possibly increasing their individual disease risk. Functional profiling of all rearranged genes within RM study group revealed significant enrichment of loci related to innate immunity and immunoregulatory pathways essential for immune tolerance at fetomaternal interface. As a major finding, we report a multicopy duplication (61.6 kb) at 5p13.3 conferring increased maternal risk to RM in Estonia and Denmark (meta-analysis, n = 309/205, odds ratio = 4.82, P = 0.012). Comparison to Estonian population-based cohort (total, n = 1000) confirmed the risk for Estonian female cases (P = 7.9 × 10(-4) ). Datasets of four cohorts from the Database of Genomic Variants (total, n = 5,846 subjects) exhibited similar low duplication prevalence worldwide (0.7%-1.2%) compared to RM cases of this study (6.6%-7.5%). The CNV disrupts PDZD2 and GOLPH3 genes predominantly expressed in placenta and it may represent a novel risk factor for pregnancy complications.