Abstract
The incidence of stillbirth in Sweden has essentially remained constant since the 1980’s, and despite thorough investigation, many cases remain unexplained. It has been suggested that a proportion of stillbirth cases is caused by heart disease, mainly channelopathies. The aim of this study was to analyze DNA from 290 stillbirth cases without chromosomal abnormalities for pathogenic single nucleotide variants (SNVs) in 70 genes associated with cardiac channelopathies and cardiomyopathies. The HaloPlex Target Enrichment System (Agilent Technologies) was utilized to prepare sequencing libraries which were sequenced on the Illumina NextSeq platform. We found that 12.1% of the 290 investigated stillbirth cases had one (n = 31) or two (n = 4) variants with evidence supporting pathogenicity, i.e. loss-of-function variants (nonsense, frameshift, splice site substitutions), evidence from functional studies, or previous identification of the variants in affected individuals. Regarding identified putative pathogenic variants in genes associated with channelopathies, the prevalence was significantly higher in the stillbirth cohort (n = 23, 7.93%) than the corresponding prevalence of the same variants in the non-Finnish European population of the Exome Aggregation Consortium (2.70%, p<0.001) and SweGen, (2.30%, p<0.001). Our results give further support to the hypothesis that cardiac channelopathies might contribute to stillbirth. Screening for pathogenic SNVs in genes associated with heart disease might be a valuable complement for stillbirth cases where today’s conventional investigation does not reveal the underlying cause of fetal demise.
Highlights
The incidence of stillbirth in Sweden, defined as fetal death occurring at completed gestational week 22 or later, has essentially remained constant at approximately 3–4 per 1 000 live births since the 1980’s [1]
As KCNQ1 was the gene in which most putative pathogenic single nucleotide variants (SNVs) were identified in the stillbirth cohort (n = 5), all missense and LoF variants recorded in ExAC Non-Finnish European (NFE) were systematically searched for in ClinVar, to get an approximation of how common pathogenic SNVs are in the European population for this gene
A Monte Carlo permutation test with 10 000 iterations was performed to compare the proportion of pathogenic SNVs in the stillbirth cohort to ExAC NFE across all 70 genes included in the gene panel
Summary
The incidence of stillbirth in Sweden, defined as fetal death occurring at completed gestational week 22 or later, has essentially remained constant at approximately 3–4 per 1 000 live births since the 1980’s [1]. Stillbirth can be caused by several factors, such as infections, placental. Putative pathogenic variants in stillbirth in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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