2. Academic Validation
  3. De Novo SOX4 Variants Cause a Neurodevelopmental Disease Associated with Mild Dysmorphism

De Novo SOX4 Variants Cause a Neurodevelopmental Disease Associated with Mild Dysmorphism

  • Am J Hum Genet. 2019 Feb 7;104(2):246-259. doi: 10.1016/j.ajhg.2018.12.014.
Ash Zawerton 1,  Baojin Yao 2,  J Paige Yeager 3,  Tommaso Pippucci 4,  Abdul Haseeb 3,  Joshua D Smith 5,  Lisa Wischmann 6,  Susanne J Kühl 6,  John C S Dean 7,  Daniela T Pilz 8,  Susan E Holder 9,  Deciphering Developmental Disorders Study 10,  University of Washington Center for Mendelian Genomics 5,  Alisdair McNeill 11,  Claudio Graziano 12,  Véronique Lefebvre 13
Affiliations

Affiliations

  • 1 Department of Inflammation and Immunity, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA.
  • 2 Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun 130117, China.
  • 3 Department of Surgery/Division of Orthopaedic Surgery, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 4 Medical Genetics Unit, Policlinico S. Orsola-Malpighi, 40138 Bologna, Italy.
  • 5 Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
  • 6 Institute of Biochemistry and Molecular Biology, Ulm University, 89018 Ulm, Germany.
  • 7 Department of Medical Genetics, Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB25 2ZA, Scotland, UK.
  • 8 West of Scotland Genetics Services, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK; and Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
  • 9 London North West Healthcare NHS Trust, Northwick Park Hospital, Harrow HA1 3UJ, UK.
  • 10 Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
  • 11 Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield Children's Hospital, Sheffield, South Yorkshire S11 9LE, UK.
  • 12 Medical Genetics Unit, Policlinico S. Orsola-Malpighi, 40138 Bologna, Italy. Electronic address: [email protected].
  • 13 Department of Surgery/Division of Orthopaedic Surgery, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Electronic address: [email protected].
PMID: 30661772 DOI: 10.1016/j.ajhg.2018.12.014
Abstract

SOX4, together with SOX11 and SOX12, forms group C of SRY-related (SOX) transcription factors. They play key roles, often in redundancy, in multiple developmental pathways, including neurogenesis and skeletogenesis. De novo SOX11 heterozygous mutations have been shown to cause intellectual disability, growth deficiency, and dysmorphic features compatible with mild Coffin-Siris syndrome. Using trio-based exome sequencing, we here identify de novo SOX4 heterozygous missense variants in four children who share developmental delay, intellectual disability, and mild facial and digital morphological abnormalities. SOX4 is highly expressed in areas of active neurogenesis in human fetuses, and sox4 knockdown in Xenopus embryos diminishes brain and whole-body size. The SOX4 variants cluster in the highly conserved, SOX family-specific HMG domain, but each alters a different residue. In silico tools predict that each variant affects a distinct structural feature of this DNA-binding domain, and functional assays demonstrate that these SOX4 proteins carrying these variants are unable to bind DNA in vitro and transactivate SOX reporter genes in cultured cells. These variants are not found in the gnomAD database of individuals with presumably normal development, but 12 other SOX4 HMG-domain missense variants are recorded and all demonstrate partial to full activity in the reporter assay. Taken together, these findings point to specific SOX4 HMG-domain missense variants as the cause of a characteristic human neurodevelopmental disorder associated with mild facial and digital dysmorphism.

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