ORIGINAL RESEARCH article
Front. Genet.
Sec. Human and Medical Genomics
Volume 16 - 2025 | doi: 10.3389/fgene.2025.1626890
Novel estrogen-related gene variants identified by whole-exome sequencing in pregnancy-associated intrahepatic cholestasis
Provisionally accepted
Xianxian Liu*
Hua Lai
Siming XinJinliang ZhangYang HuWenjuan FanHong WanBowen Chen
Yang ZouXiaoming Zeng*- Jiangxi Maternal and Child Health Hospital, Nanchang, China
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Intrahepatic cholestasis of pregnancy (ICP) is associated with an increased risk of adverse fetal outcomes, including fetal morbidity and mortality. It is a complex liver disorder influenced by genetic interactions, estrogen levels, and environmental factors. Although elevated estrogen levels are known to contribute to ICP pathogenesis, the role of genetic variants in estrogen-related genes remains poorly characterized. Accordingly, we conducted whole-exome sequencing in 249 patients with ICP, focusing on eight key estrogen-related genes (ESR1/2, CYP17A1/19A1, CYP1A2/1B1/3A4, and COMT). Variants were validated by Sanger sequencing and functionally characterized using comprehensive bioinformatics analyses (PolyPhen-2, SIFT, and MutationTaster) combined with molecular modeling. Our whole-exome sequencing analysis of 249 patients with ICP identified 235 variants across eight estrogen-related genes, with three novel CYP17A1 missense mutations (p.Pro28Thr, p.Phe93Leu, and p.Arg347Leu) demonstrating particularly significant findings. These variants exhibited the following characteristics: (1) complete absence in 1,237 controls and all public genomic databases (1000 Genomes, ExAC, dbSNP); (2) evolutionary conservation of the affected residues, with unanimous pathogenic predictions from all algorithms (PolyPhen-2: damaging; SIFT: deleterious; MutationTaster: disease-causing); and (3) molecular modeling demonstrating structural perturbations in critical functional domains, including steroid-binding and redox partner interaction sites. Furthermore, analysis of placental tissue revealed significantly reduced CYP17A1 expression in ICP cases versus controls (P<0.05), suggesting functional impairment of estrogen metabolic pathways. We identified three novel pathogenic CYP17A1 variants associated with ICP through whole-exome sequencing, elucidated their structural and functional effects on estrogen metabolism, and demonstrated significantly reduced placental CYP17A1 expression, thereby providing crucial insights into the genetic basis of ICP pathogenesis.
Keywords: Intrahepatic cholestasis of pregnancy, Whole-exome sequencing, Estrogenrelated genes, CYP17A1 gene, Novel variants
Received: 12 May 2025; Accepted: 30 Jul 2025.
Copyright: © 2025 Liu, Lai, Xin, Zhang, Hu, Fan, Wan, Chen, Zou and Zeng. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Xianxian Liu, Jiangxi Maternal and Child Health Hospital, Nanchang, China
Xiaoming Zeng, Jiangxi Maternal and Child Health Hospital, Nanchang, China
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