ArticleAmerican journal of human genetics2020
De Novo SOX6 Variants Cause a Neurodevelopmental Syndrome Associated with ADHD, Craniosynostosis, and Osteochondromas.
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Article in American journal of human genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers, 2 of them syntheses that pooled it.
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20citing papers in PubMed, 2 pooled it
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Who cites it
20 citing papers in PubMed, 2 syntheses or guidelines pooled it, 34 citations in OpenAlex.
- Genetics versus environment in the pathophysiology of sagittal synostosis.Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery · 2026Pooled it
- Review of Recurrently Mutated Genes in Craniosynostosis Supports Expansion of Diagnostic Gene Panels.Genes · 2023Pooled it
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- STORIES: learning cell fate landscapes from spatial transcriptomics using optimal transport.Nature methods · 2026Article
- Early exposure to PFAS disrupts neuro-muscular development in zebrafish embryos.bioRxiv : the preprint server for biology · 2026Article
- Sox5 controls cell cycle progression in intermediate progenitor cells during dentate gyrus development.Frontiers in cell and developmental biology · 2026Article
- Identification of novel germline mutations in FUT7 and EXT1 linked with hereditary multiple exostoses.Oncogene · 2025Article
- Article
- Molecular Analysis of the Differential Activity of Sox8 and Sox10 in Oligodendroglial Cells.International journal of molecular sciences · 2024Article
- Defining cis-regulatory elements and transcription factors that control human cortical interneuron development.iScience · 2024Article
- Association ofOpen medicine (Warsaw, Poland) · 2024Article
- SRY-box Transcription Factor 6 Is Expressed Not Only in the Dorsal but Also in the Ventral Zone of the Neural Tube and Is Highly Expressed in the Notochord and Chordoma.Acta histochemica et cytochemica · 2023Article
- Genetic diagnosis for adult patients at a genetic clinic.Cold Spring Harbor molecular case studies · 2022Article
- Increased Serum Levels of miR-125b and miR-132 in Fragile X Syndrome: A Preliminary Study.Neurology. Genetics · 2022Article
- Neurodevelopmental disorder with dystonia due to SOX6 mutations.Molecular genetics & genomic medicine · 2022Article
- Interplay of SOX transcription factors and microRNAs in the brain under physiological and pathological conditions.Neural regeneration research · 2022Review
- An additional whole-exome sequencing study in 102 panel-undiagnosed patients: A retrospective study in a Chinese craniosynostosis cohort.Frontiers in genetics · 2022Article
- Evaluating the performance of a clinical genome sequencing program for diagnosis of rare genetic disease, seen through the lens of craniosynostosis.Genetics in medicine : official journal of the American College of Medical Genetics · 2021Article
- Improving diagnostics of rare genetic diseases with NGS approaches.Journal of community genetics · 2021Article
- SOX Transcription Factors as Important Regulators of Neuronal and Glial Differentiation During Nervous System Development and Adult Neurogenesis.Frontiers in molecular neuroscience · 2021Review
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Authors and funding
58 authors at 20 institutions in 7 countries.
Dara TolchinDepartment of Surgery, Division of Orthopaedic Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Jessica P YeagerDepartment of Surgery, Division of Orthopaedic Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Priya PrasadDepartment of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Naghmeh DorraniDivision of Medical Genetics, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Alvaro Serrano RussiDivision of Medical Genetics, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
Julian A Martinez-AgostoDivision 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.
Abdul HaseebDepartment of Surgery, Division of Orthopaedic Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Marco AngelozziDepartment of Surgery, Division of Orthopaedic Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
G W E SantenDepartment of Clinical Genetics, Leiden University Medical Centre, 2300 LC Leiden, the Netherlands.
Claudia RuivenkampDepartment of Clinical Genetics, Leiden University Medical Centre, 2300 LC Leiden, the Netherlands.
Saadet Mercimek-AndrewsDivision 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.
Christel DepienneInstitute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.
Alma KuechlerInstitute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.
Barbara MikatInstitute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.
Hermann-Josef LudeckeInstitute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; Institute für Humangenetik, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität, 40225 Düsseldorf, Germany.
Frederic BilanNeurovascular 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.
Gwenael Le GuyaderNeurovascular 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.
Brigitte Gilbert-DussardierNeurovascular 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.
Boris KerenAssistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Département de Génétique, 75013 Paris, France.
Solveig HeideAssistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Département de Génétique, 75013 Paris, France.
Damien HayeService de Génétique, Centre Hospitalier Universitaire de Nice Hôpital de l'Archet 2,151 route Saint Antoine de la Ginestière, 062002 Nice, France.
Hilde Van EschCenter for Human Genetics, University Hospitals Leuven, 3000 Leuven, Belgium.
Liesbeth KeldermansLaboratory for Molecular Diagnosis, Center for Human Genetics, University Hospitals Leuven, 3000 Leuven, Belgium.
Damara OrtizUniversity of Pittsburgh Medical Center, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
Emily LancasterUniversity of Pittsburgh Medical Center, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
Ian D KrantzRoberts Individualized Medical Genetics Center, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Bryan L KrockDivision of Genomic Diagnostics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Kieran B PechterDivision of Genomic Diagnostics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Alexandre ArkaderDepartment of Surgery, Division of Orthopaedic Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Livija MedneRoberts Individualized Medical Genetics Center, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Elizabeth T DeCheneDivision of Genomic Diagnostics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Eduardo CalpenaMRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
Giada MelistaccioMRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
Andrew O M WilkieMRC 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.
Mohnish SuriClinical Genetics Service, Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham NG5 1PB, UK.
Nicola FouldsWessex Clinical Genetics Services, University Hospital Southampton NHS Foundation Trust, Southampton SO16 5YA, UK.
Genomics England Research Consortium
Amber BegtrupGeneDx, Gaithersburg, MD 20877, USA.
Lindsay B HendersonGeneDx, Gaithersburg, MD 20877, USA.
Cara ForsterGeneDx, Gaithersburg, MD 20877, USA.
Patrick ReedGeneDx, Gaithersburg, MD 20877, USA.
Marie T McDonaldDivision of Medical Genetics, Department of Pediatrics, Duke University, Durham, NC 27707, USA.
Allyn McConkie-RosellDivision of Medical Genetics, Department of Pediatrics, Duke University, Durham, NC 27707, USA.
Julien ThevenonService 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.
Pauline Le TannoService 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.
Charles CouttonService 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.
Anne C H TsaiSection of Genetics, Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO 80045, USA.
Sarah StewartSection of Genetics, Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO 80045, USA.
Ales MaverClinical Institute of Medical Genetics, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia.
Rudolf GorazdClinical Institute of Medical Genetics, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia.
Olivier PichonCentre Hospitalier Universitaire Nantes, Service de Génétique Médicale, 44000 Nantes, France.
Mathilde NizonCentre Hospitalier Universitaire Nantes, Service de Génétique Médicale, 44000 Nantes, France; Université de Nantes, CNRS, INSERM, L'Institut du Thorax, 44000 Nantes, France.
Benjamin CognéCentre Hospitalier Universitaire Nantes, Service de Génétique Médicale, 44000 Nantes, France; Université de Nantes, CNRS, INSERM, L'Institut du Thorax, 44000 Nantes, France.
Bertrand IsidorCentre Hospitalier Universitaire Nantes, Service de Génétique Médicale, 44000 Nantes, France; Université de Nantes, CNRS, INSERM, L'Institut du Thorax, 44000 Nantes, France.
Dominique Martin-CoignardService de Cytogénétique, Centre Hospitalier Universitaire de Le Mans, 72037 Le Mans, France.
Radka StoevaService de Cytogénétique, Centre Hospitalier Universitaire de Le Mans, 72037 Le Mans, France.
Véronique LefebvreDepartment of Surgery, Division of Orthopaedic Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Electronic address: lefebvrev1@email.chop.edu.
Cédric Le CaignecCentre 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.
Children's Hospital of Philadelphia · USCentre Hospitalier Universitaire de Nantes · FRCentre National de la Recherche Scientifique · FRCentre Hospitalier du Mans · FRDuke University · USLjubljana University Medical Centre · SIChildren's Hospital Colorado · USJohn Radcliffe Hospital · GBUniversité de Poitiers · FRUniversity of Duisburg-Essen · DEChildren's Hospital of Pittsburgh · USLeiden University · NLNottingham University Hospitals NHS Trust · GBSorbonne Université · FRUniversity of California, Los Angeles · USCentre Hospitalier Universitaire de Nice · FRCentre Hospitalier Universitaire de Toulouse · FRChildren's Hospital of Los Angeles · USDüsseldorf University Hospital · DEUniversity Hospital Southampton NHS Foundation Trust · GB
Funding
Medical Research Council MR/S006753/1Wellcome Trust
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.
Indexed as
Active Transport, Cell NucleusAdolescentAmino Acid SequenceAttention Deficit Disorder with HyperactivityBase SequenceBrainChildChild, PreschoolComputer SimulationCraniosynostosesFemaleGenomic Structural VariationHumansInfantMaleMutation, MissenseSOX6 protein, humanSOXD Transcription FactorsADHDcraniosynostosisdevelopmental delaydysmorphismgenetic varianthuman diseaseintellectual disabilityosteochondromaSOX6SOXopathy
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