title: Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin-Siris syndrome.
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.
authors.affiliation: Institute for Biochemistry and Molecular Biology, Ulm University, Ulm, Germany.
authors.forename: Annmarie
authors.initials: A
authors.lastname: Hempel
authors.affiliation: National Institute for Health Research Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Alistair T
authors.initials: AT
authors.lastname: Pagnamenta
authors.affiliation: Department of Clinical Genetics, Chapel Allerton Hospital, Leeds, UK.
authors.forename: Moira
authors.initials: M
authors.lastname: Blyth
authors.affiliation: Department of Clinical Genetics, St George's Hospital, London, UK.
authors.forename: Sahar
authors.initials: S
authors.lastname: Mansour
authors.affiliation: Department of Genetic Medicine, Floor A, Belfast City Hospital, Belfast, UK.
authors.forename: Vivienne
authors.initials: V
authors.lastname: McConnell
authors.affiliation: Laboratory of Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan.
authors.forename: Ikuyo
authors.initials: I
authors.lastname: Kou
authors.affiliation: Laboratory of Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Ikegawa
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Tsurusaki
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
authors.affiliation: Department of Neuroscience, Pediatric Neurology Unit, Tor Vergata University of Rome, Rome, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Lo-Castro
authors.affiliation: Service de génétique, CHU de Caen-Hôpital de la Côte de Nacre, Caen, France.
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Plessis
authors.affiliation: Institut fur Humangenetik, Universitatsklinikum Essen, Universitat Duisburg-Essen, Essen, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Albrecht
authors.affiliation: The Stella Maris Clinical Research Institute for Child and Adolescent Neurology and Psychiatry, Pisa, Italy.
authors.forename: Agatino
authors.initials: A
authors.lastname: Battaglia
authors.affiliation: National Institute for Health Research Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Taylor
authors.affiliation: National Institute for Health Research Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Malcolm F
authors.initials: MF
authors.lastname: Howard
authors.affiliation: Institute of Molecular Pathology, Vienna, Austria.
authors.forename: David
authors.initials: D
authors.lastname: Keays
authors.affiliation: Paediatric Neurology, Birmingham Children's Hospital, Birmingham, UK.
authors.forename: Aman Singh
authors.initials: AS
authors.lastname: Sohal
authors.affiliation: Institute for Biochemistry and Molecular Biology, Ulm University, Ulm, Germany.
authors.forename: Susanne J
authors.initials: SJ
authors.lastname: Kühl
authors.affiliation: Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford, UK.
authors.forename: Usha
authors.initials: U
authors.lastname: Kini
authors.affiliation: 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.
authors.forename: Alisdair
authors.initials: A
authors.lastname: McNeill
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000503:physiopathology; D000293:Adolescent; D000328:Adult; D000818:Animals; D002648:Child; D002675:Child, Preschool; D005145:Face / Q000002:abnormalities* / Q000503:physiopathology; D005260:Female; D055785:Gene Knockdown Techniques; D006228:Hand Deformities, Congenital / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008831:Microcephaly; D008844:Micrognathism / Q000235:genetics* / Q000503:physiopathology; D009333:Neck / Q000002:abnormalities* / Q000503:physiopathology; D065886:Neurodevelopmental Disorders / Q000235:genetics* / Q000503:physiopathology; D055751:SOXC Transcription Factors / Q000235:genetics*; D017384:Sequence Deletion; D014981:Xenopus
chemical_list: C097473:SOX11 protein, human; D055751:SOXC Transcription Factors
keywords: Clinical genetics; Copy-number; Developmental; Diagnostics tests