NPFFR2 gene compound heterozygous variants associated with preeclampsia identified by whole-exome sequencing

Background: Preeclampsia (PE) is an idiopathic disorder of pregnancy. The exact cause of PE remains unknown. Emerging evidence indicates that the cause of PE is linked to genetic factors. Therefore, the aim of this study was to identify the susceptibility genes for PE.

Methods: Nine families with severe PE were recruited. The whole-exome sequencing (WES) was performed on each family, and Sanger sequencing was used to identify the potential pathogenic genetic variants.

Results: After a rigorous bioinformatics analysis, compound heterozygous variants in the NPFFR2 gene, NM_004885.2: c.601A > G, p.Met201Val and c.995C > T, p.Ala332Val were found in the No.4 pedigree. Bioinformatics analysis showed that these sites were highly conserved among several species and were predicted to be pathogenic variants according to multiple online mutational function prediction software packages. Due to the compound heterozygous variants of NPFFR2, more bonds are generated between mutant amino acids and spatial adjacent amino acids, which may lead to more stable active conformation of protein and not easy to be degraded.

Conclusions: We demonstrated for the first time that compound heterozygous variants of the NPFFR2 gene might be potentially associated with severe PE, the results of this study provide clinicians and researchers with a better understanding of the molecular mechanisms underlying severe PE in pregnant women.