A maternal GOT1 novel variant associated with early-onset severe preeclampsia identified by whole-exome sequencing

Abstract

Background: This study wants to know the genetic cause of preeclampsia (PE) which is a leading cause of maternal and perinatal death, but the underlying molecular mechanisms that cause PE remain poorly understood. Many single nucleotide polymorphisms have been identified by genome-wide association studies and were found to be associated with PE; however, few studies have used whole-exome sequencing (WES) to identify PE variants. Methods: Five patients with severe early-onset preeclampsia (EOPE) were recruited, and WES was performed on each patient. Sanger sequencing was used to confirm the potential causative genetic variant. Results: After a stringent bioinformatics analysis, a rare variant in the GOT1 gene, c.44C > G:p.P15R, was found in one patient. Bioinformatics analysis showed that the variant site is highly conserved across several species and was predicted to be a pathogenic variant according to several online mutational function prediction software packages. Further structural biology homology modeling suggested that P15R would change the electric environment of enzymatic center, and might affect the binding affinity of substrate or product. Conclusion: We demonstrated for the first time that the variant in GOT1 may be associated with EOPE, the results of this study provide researchers and clinicians with a better understanding of the molecular mechanisms that underlie maternal severe EOPE.