Maternal serum CFHR4 protein as a potential non-invasive marker of ventricular septal defects in offspring: evidence from a comparative proteomics study.

Background: Despite advances in diagnosis of congenital heart defects, there is no non-invasive biomarker clinically available for the early detection of fetal ventricular septal defects (VSD).

Methods: This study was to profile differentially expressed proteins (DEP) in the first trimester maternal plasma samples that were collected in the 12th-14th week of gestation and identify potential biomarkers for VSD. Maternal plasma samples of ten case-control pairs of women (who had given birth to an isolated VSD infant or not) were selected from a birth cohort biospecimen bank for identifying DEPs by using high-performance liquid chromatography-tandem mass spectrometry-based comparative proteomics.

Results: There were 35 proteins with significantly different levels between cases and controls, including 9 upregulated and 26 downregulated proteins. With Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway enrichment, and protein-protein interaction analyses, most of the DEPs were clustered in pathways related to B cell-mediated immune responses, complement activation, and phagocytosis. Three DEPs were validated using enzyme-linked immunosorbent assay in another set of samples consisting of 31 cases and 33 controls. And CFHR4, a key regulator in complement cascades, was found to be significantly upregulated in cases as compared to controls.

Conclusions: Subsequent logistic regression and receiver operating characteristic analysis suggested maternal serum CFHR4 as a promising biomarker of fetal VSD. Further studies are warranted to verify the findings.