Published September 16, 2022
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Functional characteristics of a broad spectrum of TBX6 variants in Mayer-Rokitansky-Küster-Hauser syndrome.

Creators

  • 1. 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.
  • 2. Peking Union Medical College
  • 3. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Medical Scientist Training Program, Baylor College of Medicine, Houston, TX.
  • 4. Baylor College of Medicine
  • 5. 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.
  • 6. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
  • 7. Department of Gynecology and Obstetrics, Research Centre for Women's Health, Tübingen University Hospital, Tübingen, Germany.
  • 8. 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.
  • 9. Shandong University
  • 10. Department of Obstetrics and Gynecology, The 3rd Affiliated Hospital of Shenzhen University, Luohu Hospital, Shenzhen, Guangdong, China.
  • 11. Shenzhen University
  • 12. Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
  • 13. University of Geneva
  • 14. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX.
  • 15. Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China.
  • 16. 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.
  • 17. Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
  • 18. 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.
  • 19. 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.
  • 20. National and Kapodistrian University of Athens
  • 21. 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.
  • 22. Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of Sao Paulo, Sao Paulo, Brazil.
  • 23. University of São Paulo
  • 24. 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.
  • 25. Institute for Bioinnovation, Biomedical Sciences Research Center Alexander Fleming, Vari, Athens, Greece.
  • 26. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Baylor Genetics, Houston, TX.
  • 27. 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.
  • 28. 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.
  • 29. 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. Electronic address: dr.wunan@pumch.cn.
  • 30. 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. Electronic address: zhu_julie@vip.sina.com.

Description

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. 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. 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. 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. Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.
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