{
  "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.",
  "authors": [
    {
      "affiliations": [
        "National Clinical Research Center for Obstetric & Gynecologic Diseases, Department of Obstetrics and Gynecology, Peking UnionMedical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China"
      ],
      "name": "Na Chen"
    },
    {
      "affiliations": [
        "Department of Dermatology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China"
      ],
      "name": "Xi Cheng"
    },
    {
      "affiliations": [
        "Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China",
        "State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China",
        "Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Science, Beijing, China"
      ],
      "name": "Sen Zhao"
    },
    {
      "affiliations": [
        "Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China"
      ],
      "name": "Hengqiang Zhao"
    },
    {
      "affiliations": [
        "Department of Obstetrics and Gynaecology, The 3rd Affiliated Hospital of Shenzhen University, Luohu Hospital, Shenzhen, Guangdong, China"
      ],
      "name": "Chenglu Qin"
    },
    {
      "affiliations": [
        "Institute of Biomedical Big Data, Wenzhou Medical University, Wenzhou, China"
      ],
      "name": "Yaru Zhang"
    },
    {
      "affiliations": [
        "Peking Union Medical College Hospital, Eight-year Medical Doctor Program, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"
      ],
      "name": "Xijuan Lin"
    },
    {
      "affiliations": [
        "Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China",
        "State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China",
        "Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Science, Beijing, China"
      ],
      "name": "Qing Li"
    },
    {
      "affiliations": [
        "National Clinical Research Center for Obstetric & Gynecologic Diseases, Department of Obstetrics and Gynecology, Peking UnionMedical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China",
        "Department of Pathology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China"
      ],
      "name": "Yuan Wang"
    },
    {
      "affiliations": [
        "National Clinical Research Center for Obstetric & Gynecologic Diseases, Department of Obstetrics and Gynecology, Peking UnionMedical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China"
      ],
      "name": "Jia Kang"
    },
    {
      "affiliations": [
        "National Clinical Research Center for Obstetric & Gynecologic Diseases, Department of Obstetrics and Gynecology, Peking UnionMedical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China"
      ],
      "name": "Jing Yu"
    },
    {
      "affiliations": [
        "National Clinical Research Center for Obstetric & Gynecologic Diseases, Department of Obstetrics and Gynecology, Peking UnionMedical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China"
      ],
      "name": "Jianbin Guo"
    },
    {
      "affiliations": [
        "National Clinical Research Center for Obstetric & Gynecologic Diseases, Department of Obstetrics and Gynecology, Peking UnionMedical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China"
      ],
      "name": "Qianqian Gao"
    },
    {
      "affiliations": [
        "National Clinical Research Center for Obstetric & Gynecologic Diseases, Department of Obstetrics and Gynecology, Peking UnionMedical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China"
      ],
      "name": "Jiali Duan"
    },
    {
      "affiliations": [
        "State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China",
        "Department of Central Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China"
      ],
      "name": "Yuchen Niu"
    },
    {
      "affiliations": [
        "Institute of Biomedical Big Data, Wenzhou Medical University, Wenzhou, Zhejiang, China"
      ],
      "name": "Jianzhong Su"
    },
    {
      "affiliations": [
        "Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China",
        "Department of Central Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China"
      ],
      "name": "Zhihong Wu"
    },
    {
      "affiliations": [
        "Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China",
        "State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China",
        "Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Science, Beijing, China"
      ],
      "name": "Terry Jianguo Zhang"
    },
    {
      "affiliations": [
        "Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China",
        "Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"
      ],
      "name": "Wanlu Liu"
    },
    {
      "affiliations": [
        "Baylor College of Medicine, Houston, Texas, USA"
      ],
      "name": "Pengfei Liu"
    },
    {
      "affiliations": [
        "National Clinical Research Center for Obstetric & Gynecologic Diseases, Department of Obstetrics and Gynecology, Peking UnionMedical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China"
      ],
      "name": "Shan Deng"
    },
    {
      "affiliations": [
        "Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China",
        "State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China",
        "Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Science, Beijing, China"
      ],
      "name": "Nan Wu"
    },
    {
      "affiliations": [
        "National Clinical Research Center for Obstetric & Gynecologic Diseases, Department of Obstetrics and Gynecology, Peking UnionMedical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China"
      ],
      "name": "Lan Zhu"
    }
  ],
  "title": "Genetic and embryonic transcriptome analyses reveal the molecular and developmental basis of Mayer-Rokitansky-Küster-Hauser syndrome",
  "uid": "fb8ab805-a3c3-5b5d-b8d6-a7620c449352"
}