2. Academic Validation
  3. De Novo SOX6 Variants Cause a Neurodevelopmental Syndrome Associated with ADHD, Craniosynostosis, and Osteochondromas

De Novo SOX6 Variants Cause a Neurodevelopmental Syndrome Associated with ADHD, Craniosynostosis, and Osteochondromas

  • Am J Hum Genet. 2020 Jun 4;106(6):830-845. doi: 10.1016/j.ajhg.2020.04.015.
Dara Tolchin 1,  Jessica P Yeager 1,  Priya Prasad 2,  Naghmeh Dorrani 3,  Alvaro Serrano Russi 4,  Julian A Martinez-Agosto 5,  Abdul Haseeb 1,  Marco Angelozzi 1,  G W E Santen 6,  Claudia Ruivenkamp 6,  Saadet Mercimek-Andrews 7,  Christel Depienne 8,  Alma Kuechler 8,  Barbara Mikat 8,  Hermann-Josef Ludecke 9,  Frederic Bilan 10,  Gwenael Le Guyader 10,  Brigitte Gilbert-Dussardier 10,  Boris Keren 11,  Solveig Heide 11,  Damien Haye 12,  Hilde Van Esch 13,  Liesbeth Keldermans 14,  Damara Ortiz 15,  Emily Lancaster 15,  Ian D Krantz 16,  Bryan L Krock 17,  Kieran B Pechter 17,  Alexandre Arkader 1,  Livija Medne 16,  Elizabeth T DeChene 17,  Eduardo Calpena 18,  Giada Melistaccio 18,  Andrew O M Wilkie 19,  Mohnish Suri 20,  Nicola Foulds 21,  Genomics England Research Consortium,  Amber Begtrup 22,  Lindsay B Henderson 22,  Cara Forster 22,  Patrick Reed 22,  Marie T McDonald 23,  Allyn McConkie-Rosell 23,  Julien Thevenon 24,  Pauline Le Tanno 24,  Charles Coutton 24,  Anne C H Tsai 25,  Sarah Stewart 25,  Ales Maver 26,  Rudolf Gorazd 26,  Olivier Pichon 27,  Mathilde Nizon 28,  Benjamin Cogné 28,  Bertrand Isidor 28,  Dominique Martin-Coignard 29,  Radka Stoeva 29,  Véronique Lefebvre 30,  Cédric Le Caignec 31
Affiliations

Affiliations

  • 1 Department of Surgery, Division of Orthopaedic Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 2 Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
  • 3 Division of Medical Genetics, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 4 Division of Medical Genetics, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
  • 5 Division of Medical Genetics, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 6 Department of Clinical Genetics, Leiden University Medical Centre, 2300 LC Leiden, the Netherlands.
  • 7 Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada; Institute of Medical Sciences, University of Toronto, Toronto, ON M5G 1X8, Canada.
  • 8 Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.
  • 9 Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; Institute für Humangenetik, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität, 40225 Düsseldorf, Germany.
  • 10 Neurovascular Unit and Cognitive Disorders (EA-3808 NEUVACOD), Université de Poitiers, 86073 Poitiers, France; Service de Génétique Clinique, Centre Hospitalier Universitaire de Poitiers, 86021 Poitiers, France.
  • 11 Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Département de Génétique, 75013 Paris, France.
  • 12 Service de Génétique, Centre Hospitalier Universitaire de Nice Hôpital de l'Archet 2,151 route Saint Antoine de la Ginestière, 062002 Nice, France.
  • 13 Center for Human Genetics, University Hospitals Leuven, 3000 Leuven, Belgium.
  • 14 Laboratory for Molecular Diagnosis, Center for Human Genetics, University Hospitals Leuven, 3000 Leuven, Belgium.
  • 15 University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
  • 16 Roberts Individualized Medical Genetics Center, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 17 Division of Genomic Diagnostics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 18 MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
  • 19 MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK; Clinical Genetics Service, Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham NG5 1PB, UK.
  • 20 Clinical Genetics Service, Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham NG5 1PB, UK.
  • 21 Wessex Clinical Genetics Services, University Hospital Southampton NHS Foundation Trust, Southampton SO16 5YA, UK.
  • 22 GeneDx, Gaithersburg, MD 20877, USA.
  • 23 Division of Medical Genetics, Department of Pediatrics, Duke University, Durham, NC 27707, USA.
  • 24 Service de Génétique, Génomique, et Procréation, Centre Hospitalier Universitaire Grenoble Alpes, 38700 La Tronche, France; INSERM 1209, CNRS UMR 5309, Institute for Advanced Biosciences, Université Grenoble Alpes, 38706 Grenoble, France.
  • 25 Section of Genetics, Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO 80045, USA.
  • 26 Clinical Institute of Medical Genetics, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia.
  • 27 Centre Hospitalier Universitaire Nantes, Service de Génétique Médicale, 44000 Nantes, France.
  • 28 Centre Hospitalier Universitaire Nantes, Service de Génétique Médicale, 44000 Nantes, France; Université de Nantes, CNRS, INSERM, L'Institut du Thorax, 44000 Nantes, France.
  • 29 Service de Cytogénétique, Centre Hospitalier Universitaire de Le Mans, 72037 Le Mans, France.
  • 30 Department of Surgery, Division of Orthopaedic Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Electronic address: lefebvrev1@email.chop.edu.
  • 31 Centre Hospitalier Universitaire Nantes, Service de Génétique Médicale, 44000 Nantes, France; Centre Hospitalier Universitaire Toulouse, Service de Génétique Médicale, 31000 Toulouse, France. Electronic address: lecaignec.c@chu-toulouse.fr.
PMID: 32442410 DOI: 10.1016/j.ajhg.2020.04.015
Abstract

SOX6 belongs to a family of 20 SRY-related HMG-box-containing (SOX) genes that encode transcription factors controlling cell fate and differentiation in many developmental and adult processes. For SOX6, these processes include, but are not limited to, neurogenesis and skeletogenesis. Variants in half of the SOX genes have been shown to cause severe developmental and adult syndromes, referred to as SOXopathies. We here provide evidence that SOX6 variants also cause a SOXopathy. Using clinical and genetic data, we identify 19 individuals harboring various types of SOX6 alterations and exhibiting developmental delay and/or intellectual disability; the individuals are from 17 unrelated families. Additional, inconstant features include attention-deficit/hyperactivity disorder (ADHD), autism, mild facial dysmorphism, craniosynostosis, and multiple osteochondromas. All variants are heterozygous. Fourteen are de novo, one is inherited from a mosaic father, and four offspring from two families have a paternally inherited variant. Intragenic microdeletions, balanced structural rearrangements, frameshifts, and nonsense variants are predicted to inactivate the SOX6 variant allele. Four missense variants occur in residues and protein regions highly conserved evolutionarily. These variants are not detected in the gnomAD control cohort, and the amino acid substitutions are predicted to be damaging. Two of these variants are located in the HMG domain and abolish SOX6 transcriptional activity in vitro. No clear genotype-phenotype correlations are found. Taken together, these findings concur that SOX6 haploinsufficiency leads to a neurodevelopmental SOXopathy that often includes ADHD and abnormal skeletal and other features.

Keywords

ADHD; SOX6; SOXopathy; craniosynostosis; developmental delay; dysmorphism; genetic variant; human disease; intellectual disability; osteochondroma.

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