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Wiley, Human Mutation, 8(35), p. 972-982

DOI: 10.1002/humu.22589

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Structural genomic variation as risk factor for idiopathic recurrent miscarriage

This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

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/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 feto-maternal 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, OR = 4.82, P = 0.012). Comparison to Estonian population-based EGCUT 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 = 5846 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.This article is protected by copyright. All rights reserved