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SOX11 variants cause a neurodevelopmental disorder with infrequent ocular malformations and hypogonadotropic hypogonadism and with distinct DNA methylation profile
Authors:Reem Al-Jawahiri  Aidin Foroutan  Jennifer Kerkhof  Haley McConkey  Michael Levy  Sadegheh Haghshenas  Kathleen Rooney  Jasmin Turner  Debbie Shears  Muriel Holder  Henrietta Lefroy  Bruce Castle  Linda M. Reis  Elena V. Semina  Katherine Lachlan  Kate Chandler  Thomas Wright
Affiliation:1. Department of Psychology, The University of Sheffield, Sheffield, United Kingdom;2. Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada;3. The Archie and Irene Verspeeten Clinical Genome Centre, London Health Sciences Foundation, London Health Sciences Centre, London, Ontario, Canada;4. Biosciences Institute, Newcastle University, Newcastle Upon Tyne, United Kingdom;5. Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom;6. Department of Clinical Genetics, Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom;7. Peninsula Clinical Genetics Service, RD&E Heavitree Hospital, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom;8. Department of Pediatrics and Children’s Research Institute, Medical College of Wisconsin, Children’s Wisconsin, Milwaukee, WI;9. Wessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom;10. Manchester Centre for Genomic Medicine, Saint Mary’s Hospital, Manchester University NHS Foundation Trust, Manchester, United Kingdom;11. Service of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital, Lausanne, Switzerland;12. Ruhr-Universitat Bochum, Abteilung für Humangenetik, Bochum, Germany;13. Clinical Genetics, Addenbrooke’s Treatment Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom;14. Clinical Genetics, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom;15. West Midlands Regional Clinical Genetics Centre and Department of Clinical Genetics, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, United Kingdom;16. Ambulanzzentrum UKSH, Institut für Humangenetik, Universitätsklinikum Schleswig-Holstein, Lübeck, Germany;17. Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India;18. Medical Genetics Laboratory, Bambino Gesu Children’s Hospital, Rome, Italy;19. Paediatric Department, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy;20. Angers University Hospital Center, Angers, France;21. Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany;22. Department of Human Genetics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland;23. EA7364 RADEME, Institute of Medical Genetics, Lille University Hospital, Lille University, Lille, France;24. Faculty of Nutritional Science, Sagami Women''s University, Sagamihara, Japan;25. Department of Medical Genetics, Osaka Women’s and Children’s Hospital, Osaka, Japan;26. Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan;27. Laboratory for Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan;28. Department of Orthopedic Surgery, Keio University School of Medicine, Keio University, Tokyo, Japan;29. Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium;30. Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium;31. Centrum voor Medische Genetica - UZ Gent, Ghent University Hospital, Gent, Belgium;32. Department of Clinical Genetics Service, University Hospitals Bristol NHS Foundation Trust, Bristol, United Kingdom;33. Department of Human Genetics, Amsterdam Reproduction & Development Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands;34. Department of Neuroscience, The Medical School, The University of Sheffield, Sheffield, United Kingdom;35. Department of Clinical Genetics, Sheffield Children’s Hospital NHS Foundation Trust, Sheffield, United Kingdom
Abstract:
PurposeThis study aimed to undertake a multidisciplinary characterization of the phenotype associated with SOX11 variants.MethodsIndividuals with protein altering variants in SOX11 were identified through exome and genome sequencing and international data sharing. Deep clinical phenotyping was undertaken by referring clinicians. Blood DNA methylation was assessed using Infinium MethylationEPIC array. The expression pattern of SOX11 in developing human brain was defined using RNAscope.ResultsWe reported 38 new patients with SOX11 variants. Idiopathic hypogonadotropic hypogonadism was confirmed as a feature of SOX11 syndrome. A distinctive pattern of blood DNA methylation was identified in SOX11 syndrome, separating SOX11 syndrome from other BAFopathies.ConclusionSOX11 syndrome is a distinct clinical entity with characteristic clinical features and episignature differentiating it from BAFopathies.
Keywords:Exome  Genome sequencing  Hypogonadism  Methylation  Neurodevelopmental disorder  SOX11
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