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STAG1 mutations cause a novel cohesinopathy characterised by unspecific syndromic intellectual disability
  1. Daphné Lehalle1,2,
  2. Anne-Laure Mosca-Boidron3,4,
  3. Amber Begtrup5,
  4. Odile Boute-Benejean6,
  5. Perrine Charles7,
  6. Megan T Cho5,
  7. Amanda Clarkson8,
  8. Orrin Devinsky9,
  9. Yannis Duffourd4,
  10. Laurence Duplomb-Jego3,4,
  11. Bénédicte Gérard10,
  12. Aurélia Jacquette7,
  13. Paul Kuentz3,4,
  14. Alice Masurel-Paulet1,2,
  15. Carey McDougall11,
  16. Sébastien Moutton12,
  17. Hilde Olivié13,
  18. Soo-Mi Park8,
  19. Anita Rauch14,
  20. Nicole Revencu15,
  21. Jean-Baptiste Rivière1,3,4,
  22. Karol Rubin16,
  23. Ingrid Simonic8,
  24. Deborah J Shears17,
  25. Thomas Smol6,18,
  26. Ana Lisa Taylor Tavares8,
  27. Paulien Terhal19,
  28. Julien Thevenon1,2,4,
  29. Koen Van Gassen19,
  30. Catherine Vincent-Delorme6,
  31. Marjolein H Willemsen20,
  32. Golder N Wilson21,
  33. Elaine Zackai12,
  34. Christiane Zweier22,
  35. Patrick Callier1,3,4,
  36. Christel Thauvin-Robinet1,2,4,
  37. Laurence Faivre1,2,4
  1. 1 Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon, Dijon, France
  2. 2 Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Interrégion Est, Centre Hospitalier Universitaire Dijon, Dijon, France
  3. 3 Laboratoire de Cytogénétique, Centre Hospitalier Universitaire Dijon, Dijon, France
  4. 4 Equipe GAD, EA4271, Faculté de Médecine, Université de Bourgogne Franche-Comté, Dijon, France
  5. 5 GeneDx, 207 Perry Parkway, Gaithersburg, Maryland, USA
  6. 6 Service de génétique clinique, CHU Lille, Lille, France
  7. 7 Genetic Department, University Hospital La Pitié Salpêtrière, Paris, France
  8. 8 Department of Clinical Genetics, Cambridge University Hospitals, Cambridge, UK
  9. 9 Epilepsy Center, NYU Langone Medical Center, New York, New York, USA
  10. 10 Laboratoire de biologie moléculaire, CHU Strasbourg, Strasbourg, France
  11. 11 Clinical Genetics Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  12. 12 Department of Clinical Genetics, Bordeaux, France
  13. 13 Department of Human Genetics and Centre for Developmental Disabilities, KU University Hospital Leuven, Leuven, Belgium
  14. 14 Institute of Medical Genetics, University of Zurich, Schwerzenbach-Zurich, Switzerland
  15. 15 Centre for Human Genetics, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
  16. 16 University of Minnesota Children's Hospital, Minneapolis, Minnesota, USA
  17. 17 Oxford Centre for Genomic Medicine Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7HE
  18. 18 Univ. Lille, RADEME (Research team on rare developmental and metabolic diseases), Lille, France
  19. 19 Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands
  20. 20 Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands
  21. 21 Department of Pediatrics, Texas Tech University Health Science Center, Lubbock, Texas, USA
  22. 22 Institute of Human Genetics, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Germany
  1. Correspondence to Professor Laurence Faivre, Service de Génétique, Hôpital d'Enfants, CHU Dijon, 14 rue Gaffarel, Dijon 21000, France; laurence.faivre{at}


Background Cohesinopathies are rare neurodevelopmental disorders arising from a dysfunction in the cohesin pathway, which enables chromosome segregation and regulates gene transcription. So far, eight genes from this pathway have been reported in human disease. STAG1 belongs to the STAG subunit of the core cohesin complex, along with five other subunits. This work aimed to identify the phenotype ascribed to STAG1 mutations.

Methods Among patients referred for intellectual disability (ID) in genetics departments worldwide, array-comparative genomic hybridisation (CGH), gene panel, whole-exome sequencing or whole-genome sequencing were performed following the local diagnostic standards.

Results A mutation in STAG1 was identified in 17 individuals from 16 families, 9 males and 8 females aged 2–33 years. Four individuals harboured a small microdeletion encompassing STAG1; three individuals from two families had an intragenic STAG1 deletion. Six deletions were identified by array-CGH, one by whole-exome sequencing. Whole-exome sequencing found de novo heterozygous missense or frameshift STAG1 variants in eight patients, a panel of genes involved in ID identified a missense and a frameshift variant in two individuals. The 17 patients shared common facial features, with wide mouth and deep-set eyes. Four individuals had mild microcephaly, seven had epilepsy.

Conclusions We report an international series of 17 individuals from 16 families presenting with syndromic unspecific ID that could be attributed to a STAG1 deletion or point mutation. This first series reporting the phenotype ascribed to mutation in STAG1 highlights the importance of data sharing in the field of rare disorders.

  • Intellectual disability
  • Cohesin
  • STAG1
  • datasharing

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  • Contributors DL wrote the paper. A-LM-B/PCa and AC/IS analysed the array CGH (patients 1 and 5), AB/MTC, BG, PK/J-BR/JT/LD-J, AR, TS and KVG analysed the WES data (patients 10–12 and 14–15, 3, 16, 8, 7, 13 and 15), OB-B, PCh/AJ, OD, AM-P, CMD, SM, HO, S-MP/ALTT, NR, DJS, PT, CV-D, MHW, GNW and CZ are the referring clinician (patients 16, 8, 11, 1, 14, 4, 2, 5, 6, 9, 15, 13, 3, 10 and 7), CT-R and LF supervised this work.

  • Competing interests MTC and AB are employees of GeneDx.

  • Patient consent Obtained.

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

  • Ethics approval Obtained.