Genetic and embryonic transcriptome analyses reveal the molecular and developmental basis of Mayer-Rokitansky-Küster-Hauser Syndrome

Authors

Na Chen
Xi Cheng
Sen Zhao
Hengqiang Zhao
Chenglu Qin
Yaru Zhang
Xijuan Lin
Qing Li
Yuan Wang
Jia Kang
Jing Yu
Jianbin Guo
Qianqian Gao
Jiali Duan
Yuchen Niu
Jianzhong Su
Zhihong Wu
Terry Jianguo Zhang
Wanlu Liu
Pengfei Liu
Shan Deng
Nan Wu
Lan Zhu

Language

English

Publication Date

11-13-2025

Journal

Journal of Medical Genetics

DOI

10.1136/jmg-2025-110805

PMID

41233206

Abstract

Background: Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is characterised by aplasia of the uterus, cervix and upper part of the vagina. The genetic aetiology remains incompletely understood.

Methods: We performed gene-level and gene set-level burden analyses based on exome sequencing/genome sequencing data from 727 probands with MRKHS and 2504 female control individuals. Single-cell RNA sequencing (scRNA-seq) was performed on human and mouse embryonic metanephros at different developmental stages. Genetic and transcriptomic data were integrated to prioritise suboptimal genetic signals, identify relevant cell types and determine key developmental stages. Potential digenic inheritance was assessed and prioritised using coexpression patterns from scRNA-seq data.

Results: We identified known MRKHS genes (PAX8, BMP7, GREB1L) and novel candidates (PAN2, AGPAT2) with exome-wide significance. Enriched biological processes included cell apoptosis and mesenchymal-to-epithelial transition. In human embryos, MRKHS-associated genes were enriched in the uterine epithelium at eight gestational weeks (w8) and Wolffian duct epithelium at w11, supporting the biological relevance of burden signals. We detected 992 digenic combinations in MRKHS, with three achieving exome-wide significance (CPSF3L/CYP2A7, AICDA/NOS1, EVC2/KANK1).

Conclusion: Our study reveals both established and novel genetic contributors to MRKHS, links them to specific embryonic cell types and stages, and highlights potential digenic inheritance patterns. Integrating genetic burden and single-cell transcriptomic data provides new insights into the complex molecular mechanisms underlying MRKHS.

Keywords

Female Urogenital Diseases and Pregnancy Complications. Genetics

Published Open-Access

yes

Recommended Citation

Chen, Na; Cheng, Xi; Zhao, Sen; et al., "Genetic and embryonic transcriptome analyses reveal the molecular and developmental basis of Mayer-Rokitansky-Küster-Hauser Syndrome" (2025). Faculty and Staff Publications. 5054.
https://digitalcommons.library.tmc.edu/baylor_docs/5054