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High incidence of recurrent copy number variants in patients with isolated and syndromic Müllerian aplasia
  1. Serena Nik-Zainal1,
  2. Reiner Strick2,
  3. Mekayla Storer1,3,
  4. Ni Huang1,
  5. Roland Rad1,
  6. Lionel Willatt4,
  7. Tomas Fitzgerald1,
  8. Vicki Martin1,3,
  9. Richard Sandford5,
  10. Nigel P Carter1,
  11. Andreas R Janecke6,7,
  12. Stefan P Renner2,
  13. Patricia G Oppelt2,
  14. Peter Oppelt2,
  15. Christine Schulze2,
  16. Sara Brucker8,
  17. Matthew Hurles1,
  18. Matthias W Beckmann2,
  19. Pamela L Strissel2,
  20. Charles Shaw-Smith1,3,9
  1. 1Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK
  2. 2University-Clinic Erlangen, Department of Obstetrics and Gynecology, Erlangen, Germany
  3. 3Institute of Child Health, London, UK
  4. 4Regional Cytogenetics Laboratory, Addenbrooke's Hospital, Cambridge, UK
  5. 5Department of Clinical Genetics, Addenbrooke's Hospital, Cambridge, UK
  6. 6Department of Pediatrics II, Innsbruck Medical University, Innsbruck, Austria
  7. 7Division of Human Genetics, Innsbruck Medical University, Innsbruck, Austria
  8. 8University-Clinic, Department of Obstetrics and Gynecology, Tübingen, Germany
  9. 9Institute of Biomedical and Clinical Science, Peninsula College of Medicine and Dentistry, University of Exeter, Barrack Road, Exeter EX2 5DW, UK
  1. Correspondence to Reiner Strick, Department of Obstetrics and Gynecology, University-Clinic Erlangen, Erlangen, Germany; reiner.strick{at}


Background Congenital malformations involving the Müllerian ducts are observed in around 5% of infertile women. Complete aplasia of the uterus, cervix, and upper vagina, also termed Müllerian aplasia or Mayer–Rokitansky–Kuster–Hauser (MRKH) syndrome, occurs with an incidence of around 1 in 4500 female births, and occurs in both isolated and syndromic forms. Previous reports have suggested that a proportion of cases, especially syndromic cases, are caused by variation in copy number at different genomic loci.

Methods In order to obtain an overview of the contribution of copy number variation to both isolated and syndromic forms of Müllerian aplasia, copy number assays were performed in a series of 63 cases, of which 25 were syndromic and 38 isolated.

Results A high incidence (9/63, 14%) of recurrent copy number variants in this cohort is reported here. These comprised four cases of microdeletion at 16p11.2, an autism susceptibility locus not previously associated with Müllerian aplasia, four cases of microdeletion at 17q12, and one case of a distal 22q11.2 microdeletion. Microdeletions at 16p11.2 and 17q12 were found in 4/38 (10.5%) cases with isolated Müllerian aplasia, and at 16p11.2, 17q12 and 22q11.2 (distal) in 5/25 cases (20%) with syndromic Müllerian aplasia.

Conclusion The finding of microdeletion at 16p11.2 in 2/38 (5%) of isolated and 2/25 (8%) of syndromic cases suggests a significant contribution of this copy number variant alone to the pathogenesis of Müllerian aplasia. Overall, the high incidence of recurrent copy number variants in all forms of Müllerian aplasia has implications for the understanding of the aetiopathogenesis of the condition, and for genetic counselling in families affected by it.

  • Copy number variation
  • Müllerian aplasia
  • MRKH
  • clinical genetics
  • molecular genetics
  • reproductive medicine

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  • SN-Z and RS contributed equally to this work.

  • Funding Other funders: Wellcome Trust; Deutsche Forschungsgemeinschaft.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the Ethics Review Board of Friedrich-Alexander-University, Erlangen-Nuremberg, Germany.

  • Provenance and peer review Not commissioned; externally peer reviewed.