Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin-Siris syndrome

  • J Med Genet. 2016 Mar;53(3):152-62. doi: 10.1136/jmedgenet-2015-103393.
Annmarie Hempel  1 ,  Alistair T Pagnamenta  2 ,  Moira Blyth  3 ,  Sahar Mansour  4 ,  Vivienne McConnell  5 ,  Ikuyo Kou  6 ,  Shiro Ikegawa  6 ,  Yoshinori Tsurusaki  7 ,  Naomichi Matsumoto  7 ,  Adriana Lo-Castro  8 ,  Ghislaine Plessis  9 ,  Beate Albrecht  10 ,  Agatino Battaglia  11 ,  Jenny C Taylor  2 ,  Malcolm F Howard  2 ,  David Keays  12 ,  Aman Singh Sohal  13 ,  DDD Collaboration ,  Susanne J Kühl  1 ,  Usha Kini  14 ,  Alisdair McNeill  15
Affiliations
  • 1. Institute for Biochemistry and Molecular Biology, Ulm University, Ulm, Germany.
  • 2. National Institute for Health Research Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
  • 3. Department of Clinical Genetics, Chapel Allerton Hospital, Leeds, UK.
  • 4. Department of Clinical Genetics, St George's Hospital, London, UK.
  • 5. Department of Genetic Medicine, Floor A, Belfast City Hospital, Belfast, UK.
  • 6. Laboratory of Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan.
  • 7. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
  • 8. Department of Neuroscience, Pediatric Neurology Unit, Tor Vergata University of Rome, Rome, Italy.
  • 9. Service de génétique, CHU de Caen-Hôpital de la Côte de Nacre, Caen, France.
  • 10. Institut fur Humangenetik, Universitatsklinikum Essen, Universitat Duisburg-Essen, Essen, Germany.
  • 11. The Stella Maris Clinical Research Institute for Child and Adolescent Neurology and Psychiatry, Pisa, Italy.
  • 12. Institute of Molecular Pathology, Vienna, Austria.
  • 13. Paediatric Neurology, Birmingham Children's Hospital, Birmingham, UK.
  • 14. Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford, UK.
  • 15. INSIGNEO Institute for in silico medicine, Sheffield University, Sheffield, UK Sheffield Institute for Translational Neuroscience, Sheffield University, Sheffield, UK Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, UK.
PMID: 26543203 DOI: 10.1136/jmedgenet-2015-103393
Abstract

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.

Keywords
Clinical genetics; Copy-number; Developmental; Diagnostics tests.