Structural genomic variation as risk factor for idiopathic recurrent miscarriage

Hum Mutat. 2014 Aug;35(8):972-82. doi: 10.1002/humu.22589. Epub 2014 Jun 24.


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.

Keywords: GOLPH3; PDZD2; fetomaternal interface; immune dysfunction; placenta; recurrent miscarriage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abortion, Habitual / genetics*
  • Abortion, Habitual / pathology
  • Adaptor Proteins, Signal Transducing / genetics*
  • Base Sequence
  • Chromosome Duplication
  • DNA Copy Number Variations*
  • Databases, Genetic
  • Denmark
  • Estonia
  • Female
  • Fetus
  • Genetic Loci
  • Genetic Predisposition to Disease
  • Genome, Human*
  • Humans
  • Immune Tolerance / genetics
  • Membrane Proteins / genetics*
  • Molecular Sequence Data
  • Neoplasm Proteins / genetics*
  • Oligonucleotide Array Sequence Analysis
  • Placenta / metabolism
  • Placenta / pathology
  • Polymorphism, Single Nucleotide
  • Pregnancy
  • Risk Factors


  • Adaptor Proteins, Signal Transducing
  • GOLPH3 protein, human
  • Membrane Proteins
  • Neoplasm Proteins
  • PDZD2 protein, human