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Functional characteristics of a broad spectrum of TBX6 variants in Mayer-Rokitansky-Küster-Hauser syndrome

  • Congcong Ma
    Affiliations
    Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetric and Gynecologic Diseases, 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
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  • Na Chen
    Affiliations
    Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetric and Gynecologic Diseases, 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
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  • Angad Jolly
    Affiliations
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX

    Medical Scientist Training Program, Baylor College of Medicine, Houston, TX
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  • Sen Zhao
    Affiliations
    Department of Orthopedic Surgery, 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

    Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
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  • Zeynep Coban-Akdemir
    Affiliations
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
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  • Weijie Tian
    Affiliations
    Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetric and Gynecologic Diseases, 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
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  • Jia Kang
    Affiliations
    Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetric and Gynecologic Diseases, 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
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  • Yang Ye
    Affiliations
    Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetric and Gynecologic Diseases, 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
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  • Yuan Wang
    Affiliations
    Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetric and Gynecologic Diseases, 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
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  • André Koch
    Affiliations
    Department of Gynecology and Obstetrics, Research Centre for Women's Health, Tübingen University Hospital, Tübingen, Germany
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  • Yuanqiang Zhang
    Affiliations
    Department of Orthopedic Surgery, 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

    Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China

    Department of Orthopedic Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China
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  • Chenglu Qin
    Affiliations
    Department of Obstetrics and Gynecology, The 3rd Affiliated Hospital of Shenzhen University, Luohu Hospital, Shenzhen, Guangdong, China
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  • Ximena Bonilla
    Affiliations
    Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
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  • Christelle Borel
    Affiliations
    Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
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  • Katharina Rall
    Affiliations
    Department of Gynecology and Obstetrics, Research Centre for Women's Health, Tübingen University Hospital, Tübingen, Germany
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  • Zefu Chen
    Affiliations
    Department of Orthopedic Surgery, 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

    Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
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  • Shalini Jhangiani
    Affiliations
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX

    Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX
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  • Yuchen Niu
    Affiliations
    Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
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  • Xiaoxin Li
    Affiliations
    Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
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  • Guixing Qiu
    Affiliations
    Department of Orthopedic Surgery, 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

    Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China

    Key Laboratory of Big Data for Spinal Deformities, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
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  • Shuyang Zhang
    Affiliations
    Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
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  • Guangnan Luo
    Affiliations
    Department of Obstetrics and Gynecology, The 3rd Affiliated Hospital of Shenzhen University, Luohu Hospital, Shenzhen, Guangdong, China
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  • Zhihong Wu
    Affiliations
    Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China

    Key Laboratory of Big Data for Spinal Deformities, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China

    Medical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
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  • Flora Bacopoulou
    Affiliations
    Center for Adolescent Medicine and UNESCO Chair in Adolescent Health Care, First Department of Pediatrics, School of Medicine, National and Kapodistrian University of Athens, Aghia Sophia Children's Hospital, Athens, Greece
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  • Efthymios Deligeoroglou
    Affiliations
    Division of Pediatric-Adolescent Gynecology and Reconstructive Surgery, 2nd Department of Obstetrics and Gynecology, School of Medicine, National and Kapodistrian University of Athens, Aretaieion Hospital, Athens, Greece
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  • Terry Jianguo Zhang
    Affiliations
    Department of Orthopedic Surgery, 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

    Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China

    Key Laboratory of Big Data for Spinal Deformities, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
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  • Carla Rosenberg
    Affiliations
    Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of Sao Paulo, Sao Paulo, Brazil
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  • Richard A. Gibbs
    Affiliations
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX

    Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX
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  • Jennifer E. Dietrich
    Affiliations
    Department of Pediatrics, Baylor College of Medicine, Houston, TX

    Department of Obstetrics and Gynecology, Texas Children's Hospital and Baylor College of Medicine, Houston, TX

    Texas Children's Hospital, Houston, TX
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  • Antigone S. Dimas
    Affiliations
    Institute for Bioinnovation, Biomedical Sciences Research Center Alexander Fleming, Vari, Athens, Greece
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  • Pengfei Liu
    Affiliations
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX

    Baylor Genetics, Houston, TX
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  • Stylianos E. Antonarakis
    Affiliations
    Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland

    Institute of Genetics and Genomics in Geneva, University of Geneva, Geneva, Switzerland
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  • Sara Y. Brucker
    Affiliations
    Department of Gynecology and Obstetrics, Research Centre for Women's Health, Tübingen University Hospital, Tübingen, Germany
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  • Jennifer E. Posey
    Affiliations
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
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  • James R. Lupski
    Affiliations
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX

    Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX

    Department of Pediatrics, Baylor College of Medicine, Houston, TX

    Texas Children's Hospital, Houston, TX
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  • Nan Wu
    Correspondence
    Correspondence and requests for materials should be addressed to Nan Wu, Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Key Laboratory of Big data for Spinal Deformities, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Beijing 100730, China
    Affiliations
    Department of Orthopedic Surgery, 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

    Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China

    Key Laboratory of Big Data for Spinal Deformities, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
    Search for articles by this author
  • Lan Zhu
    Correspondence
    Lan Zhu, Department of Obstetrics and Gynecology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Beijing 100730, China.
    Affiliations
    Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetric and Gynecologic Diseases, 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
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  • On behalf ofDeciphering Disorders Involving Scoliosis and COmorbidities (DISCO) Study Group
Published:September 18, 2022DOI:https://doi.org/10.1016/j.gim.2022.08.012

      Abstract

      Purpose

      Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is characterized by congenital absence of the uterus, cervix, and the upper part of the vagina in females. Whole-gene deletion and loss-of-function variants in TBX6 have been identified in association with MRKHS. We aimed to expand the spectrum of TBX6 variants in MRKHS and explore the biological effect of the variant alleles.

      Methods

      Rare variants in TBX6 were called from a combined multiethnic cohort of 622 probands with MRKHS who underwent exome sequencing or genome sequencing. Multiple in vitro functional experiments were performed, including messenger RNA analysis, western blotting, transcriptional activity assay, and immunofluorescence staining.

      Results

      We identified 16 rare variants in TBX6 from the combined cohort, including 1 protein-truncating variant reported in our previous study and 15 variants with unknown effects. By comparing the prevalence of TBX6 variants in the Chinese MRKHS cohort vs 1038 female controls, we observed a significant mutational burden of TBX6 in affected individuals (P = .0004, odds ratio = 5.25), suggesting a causal role of TBX6 variants in MRKHS. Of the 15 variants with uncertain effects, 7 were shown to induce a loss-of-function effect through various mechanisms. The c.423G>A (p.Leu141=) and c.839+5G>A variants impaired the normal splicing of TBX6 messenger RNA, c.422T>C (p.Leu141Pro) and c.745G>A (p.Val249Met) led to decreased protein expression, c.10C>T (p.Pro4Ser) and c.400G>A (p.Glu134Lys) resulted in perturbed transcriptional activity, and c.356G>A (p.Arg119His) caused protein mislocalization. We observed incomplete penetrance and variable expressivity in families carrying deleterious variants, which indicates a more complex genetic mechanism than classical Mendelian inheritance.

      Conclusion

      Our study expands the mutational spectrum of TBX6 in MRKHS and delineates the molecular pathogenesis of TBX6 variants, supporting the association between deleterious variants in TBX6 and MRKHS.

      Keywords

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