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Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin–Siris syndrome
  1. Annmarie Hempel1,
  2. Alistair T Pagnamenta2,
  3. Moira Blyth3,
  4. Sahar Mansour4,
  5. Vivienne McConnell5,
  6. Ikuyo Kou6,
  7. Shiro Ikegawa6,
  8. Yoshinori Tsurusaki7,
  9. Naomichi Matsumoto7,
  10. Adriana Lo-Castro8,
  11. Ghislaine Plessis9,
  12. Beate Albrecht10,
  13. Agatino Battaglia11,
  14. Jenny C Taylor2,
  15. Malcolm F Howard2,
  16. David Keays12,
  17. Aman Singh Sohal13,
  18. DDD collaboration,
  19. Susanne J Kühl1,
  20. Usha Kini14,
  21. Alisdair McNeill15,16,17
  1. 1Institute for Biochemistry and Molecular Biology, Ulm University, Ulm, Germany
  2. 2National Institute for Health Research Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
  3. 3Department of Clinical Genetics, Chapel Allerton Hospital, Leeds, UK
  4. 4Department of Clinical Genetics, St George's Hospital, London, UK
  5. 5Department of Genetic Medicine, Floor A, Belfast City Hospital, Belfast, UK
  6. 6Laboratory of Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan
  7. 7Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
  8. 8Department of Neuroscience, Pediatric Neurology Unit, Tor Vergata University of Rome, Rome, Italy
  9. 9Service de génétique, CHU de Caen—Hôpital de la Côte de Nacre, Caen, France
  10. 10Institut fur Humangenetik, Universitatsklinikum Essen, Universitat Duisburg-Essen, Essen, Germany
  11. 11The Stella Maris Clinical Research Institute for Child and Adolescent Neurology and Psychiatry, Pisa, Italy
  12. 12Institute of Molecular Pathology, Vienna, Austria
  13. 13Paediatric Neurology, Birmingham Children's Hospital, Birmingham, UK
  14. 14Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford, UK
  15. 15INSIGNEO Institute for in silico medicine, Sheffield University, Sheffield, UK
  16. 16Sheffield Institute for Translational Neuroscience, Sheffield University, Sheffield, UK
  17. 17Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, UK
  1. Correspondence to Dr Alisdair McNeill, Sheffield Institute for Translational Neuroscience, 385a Glossop Road, Sheffield, South Yorkshire S11 9LE, UK; a.mcneill{at}


Background SOX11 is a transcription factor proposed to play a role in brain development. The relevance of SOX11 to human developmental disorders was suggested by a recent report of SOX11 mutations in two patients with Coffin–Siris syndrome. Here we further investigate the role of SOX11 variants in neurodevelopmental disorders.

Methods We used array based comparative genomic hybridisation and trio exome sequencing to identify children with intellectual disability who have deletions or de novo point mutations disrupting SOX11. The pathogenicity of the SOX11 mutations was assessed using an in vitro gene expression reporter system. Loss-of-function experiments were performed in xenopus by knockdown of Sox11 expression.

Results We identified seven individuals with chromosome 2p25 deletions involving SOX11. Trio exome sequencing identified three de novo SOX11 variants, two missense (p.K50N; p.P120H) and one nonsense (p.C29*). The biological consequences of the missense mutations were assessed using an in vitro gene expression system. These individuals had microcephaly, developmental delay and shared dysmorphic features compatible with mild Coffin–Siris syndrome. To further investigate the function of SOX11, we knocked down the orthologous gene in xenopus. Morphants had significant reduction in head size compared with controls. This suggests that SOX11 loss of function can be associated with microcephaly.

Conclusions We thus propose that SOX11 deletion or mutation can present with a Coffin–Siris phenotype.

  • Developmental
  • Clinical genetics
  • Copy-number
  • Diagnostics tests

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