Structural genomic variation as risk factor for idiopathic recurrent miscarriage.
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.
Human Molecular Genetics Research Group, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
Liina
L
Nagirnaja
Priit
P
Palta
Laura
L
Kasak
Kristiina
K
Rull
Ole B
OB
Christiansen
Henriette S
HS
Nielsen
Rudi
R
Steffensen
Tõnu
T
Esko
Maido
M
Remm
Maris
M
Laan
D000026:Abortion, Habitual / Q000235:genetics* / Q000473:pathology; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D001483:Base Sequence; D015815:Cell Adhesion Molecules; D058674:Chromosome Duplication; D056915:DNA Copy Number Variations; D030541:Databases, Genetic; D003718:Denmark; D004957:Estonia; D005260:Female; D005333:Fetus; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010920:Placenta / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D012307:Risk Factors
D048868:Adaptor Proteins, Signal Transducing; D015815:Cell Adhesion Molecules; C429024:GOLPH3 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C423943:PDZD2 protein, human
GOLPH3; PDZD2; fetomaternal interface; immune dysfunction; placenta; recurrent miscarriage