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Original research
Consolidation of the clinical and genetic definition of a SOX4-related neurodevelopmental syndrome
  1. Marco Angelozzi1,
  2. Anirudha Karvande1,
  3. Arnaud N Molin1,
  4. Alyssa L Ritter2,
  5. Jacqueline M M Leonard2,
  6. Juliann M Savatt3,
  7. Kristen Douglass3,
  8. Scott M Myers3,
  9. Mina Grippa4,
  10. Dara Tolchin1,
  11. Elaine Zackai2,
  12. Sarah Donoghue2,
  13. Anna C E Hurst5,
  14. Maria Descartes5,
  15. Kirstin Smith5,
  16. Danita Velasco6,
  17. Andrew Schmanski6,
  18. Amy Crunk7,
  19. Mari J Tokita7,
  20. Iris M de Lange8,
  21. Koen van Gassen8,
  22. Hannah Robinson9,
  23. Katie Guegan9,
  24. Mohnish Suri10,
  25. Chirag Patel11,
  26. Marie Bournez12,
  27. Laurence Faivre13,
  28. Frédéric Tran-Mau-Them14,15,
  29. Janice Baker16,
  30. Noelle Fabie16,
  31. K Weaver17,
  32. Amelle Shillington17,
  33. Robert J Hopkin18,
  34. Daniela Q C.M Barge-Schaapveld19,
  35. Claudia AL Ruivenkamp20,
  36. Regina Bökenkamp21,
  37. Samantha Vergano22,
  38. Maria Noelia Seco Moro23,
  39. Aranzazu Díaz de Bustamante24,
  40. Vinod K Misra25,26,
  41. Kelly Kennelly27,
  42. Caleb Rogers28,
  43. Jennifer Friedman29,30,31,32,
  44. Kristen M Wigby29,30,
  45. Jerica Lenberg30,
  46. Claudio Graziano29,30,31,32,33,
  47. Rebecca C Ahrens-Nicklas2,
  48. Veronique Lefebvre1
  1. 1Surgery/Division of Orthopaedic Surgery, The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania, USA
  2. 2Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  3. 3Autism & Developmental Medicine Institute, Geisinger, Danville, Pennsylvania, USA
  4. 4U.O. Genetica Medica, Universita di Bologna, Bologna, Italy
  5. 5Department of Genetics, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA
  6. 6Department of Pediatrics, University of Nebraska Medical Center, Omaha, Nebraska, USA
  7. 7GeneDx Inc, Gaithersburg, Maryland, USA
  8. 8Department of Medical Genetics, University Medical Centre Utrecht Brain Centre, Utrecht, The Netherlands
  9. 9Exeter Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
  10. 10Clinical Genetics, Nottingham University Hospitals NHS Trust, Nottingham, UK
  11. 11Genetic Health Queensland, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia
  12. 12Centres de référence Anomalies du Développement et Syndrome Malformatifs, Centre Hospitalier Universitaire de Dijon, Dijon, France
  13. 13Centre de Génétique, Centre Hospitalier Universitaire de Dijon Hôpital d'Enfants, Dijon, France
  14. 14Genetics of Developmental Disorders, INSERM - Bourgogne Franche-Comté University, UMR 1231 GAD Team, Dijon, France
  15. 15Functional Unit 6254 Innovation in Genomic Diagnosis of Rare Diseases, CHU Dijon Bourgogne, Dijon, France
  16. 16Genomics and Genetic Medicine, Children's Minnesota, Minneapolis, Minnesota, USA
  17. 17Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  18. 18Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  19. 19Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
  20. 20Laboratory for Diagnostic Genome Analyses, Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
  21. 21Department of Pediatric Cardiology, Leiden University Medical Center, Leiden, The Netherlands
  22. 22Division of Medical Genetics and Metabolism, Children's Hospital of The King's Daughters, Norfolk, Virginia, USA
  23. 23Clinical Analysis Department, Hospital Universitario de Móstoles, Mostoles, Spain
  24. 24Department of Genetics, Hospital Universitario de Móstoles, Mostoles, Spain
  25. 25Department of Pediatrics, Division of Genetic, Genomic, and Metabolic Disorders, Children's Hospital of Michigan, Detroit, Michigan, USA
  26. 26Discipline of Pediatrics, Central Michigan University, Mount Pleasant, Michigan, USA
  27. 27Department of Pediatrics, Children's Hospital of Michigan, Detroit, Michigan, USA
  28. 28Department of Molecular and Medical Genetics, Oregon Health & Science University School of Medicine, Portland, Oregon, USA
  29. 29Department of Pediatrics, University of California San Diego, San Diego, California, USA
  30. 30Division of Genetics/Dysmorphology and Institute for Genomic Medicine, Rady Children's Hospital, San Diego, California, USA
  31. 31Department of Neurosciences, University of California San Diego, San Diego, California, USA
  32. 32Division of Neurology, Rady Children's Hospital, San Diego, California, USA
  33. 33U.O. Genetica Medica, AUSL della Romagna Rimini, Cesena, Italy
  1. Correspondence to Dr Claudio Graziano, U.O. Genetica Medica, AUSL della Romagna Rimini, 47521, Cesena, Italy; claudio.graziano2{at}auslromagna.it; Dr Rebecca C Ahrens-Nicklas, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; AhrensNicklasR{at}chop.edu; Dr Veronique Lefebvre, Surgery/Division of Orthopaedic Surgery, The Children's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USA; lefebvrev1{at}chop.edu

Abstract

Background A neurodevelopmental syndrome was recently reported in four patients with SOX4 heterozygous missense variants in the high-mobility-group (HMG) DNA-binding domain. The present study aimed to consolidate clinical and genetic knowledge of this syndrome.

Methods We newly identified 17 patients with SOX4 variants, predicted variant pathogenicity using in silico tests and in vitro functional assays and analysed the patients’ phenotypes.

Results All variants were novel, distinct and heterozygous. Seven HMG-domain missense and five stop-gain variants were classified as pathogenic or likely pathogenic variant (L/PV) as they precluded SOX4 transcriptional activity in vitro. Five HMG-domain and non-HMG-domain missense variants were classified as of uncertain significance (VUS) due to negative results from functional tests. When known, inheritance was de novo or from a mosaic unaffected or non-mosaic affected parent for patients with L/PV, and from a non-mosaic asymptomatic or affected parent for patients with VUS. All patients had neurodevelopmental, neurological and dysmorphic features, and at least one cardiovascular, ophthalmological, musculoskeletal or other somatic anomaly. Patients with L/PV were overall more affected than patients with VUS. They resembled patients with other neurodevelopmental diseases, including the SOX11-related and Coffin-Siris (CSS) syndromes, but lacked the most specific features of CSS.

Conclusion These findings consolidate evidence of a fairly non-specific neurodevelopmental syndrome due to SOX4 haploinsufficiency in neurogenesis and multiple other developmental processes.

  • genetic variation
  • congenital
  • hereditary
  • gene expression regulation
  • neonatal diseases
  • abnormalities

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. De-identified individual participant data and in vitro study materials, such as SOX4 variant expression plasmids, will be made available on request to the corresponding authors, subject to the participant data sharing plan and consent provided.

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Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. De-identified individual participant data and in vitro study materials, such as SOX4 variant expression plasmids, will be made available on request to the corresponding authors, subject to the participant data sharing plan and consent provided.

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Footnotes

  • CG, RCA-N and VL are joint senior authors.

  • Contributors MA, CG, RCA-N and VL designed this study. MA, DT and AK performed most of the in silico and in vitro functional tests. MA, AK, ANM, ALR, JL, CG, RCA-N and VL analysed the data and wrote the manuscript. All other authors helped recruit patients and provided clinical information. All authors read, provided feedback and approved the manuscript. RCA-N and VL are guarantors of the overall content of the paper.

  • Funding This work was funded by the Children’s Hospital of Philadelphia (VL and RAN), National Institute of Health NIAMS R01-AR68308 grant (VL), National Institute of Health NINDS K08-NS105865 grant (RAN) and National Institute of Health NIMH R01MH074090 and U01MH119705 grants (SMM). MB and LF are members of the European Reference Network for Developmental Anomalies and Intellectual Disability (ERN-ITHACA). Genome sequencing was funded for one patient by an internal grant from Children’s of Alabama and the HudsonAlpha Institute for Biotechnology Clinical Services Laboratory (ACEH, MD, KS). The inclusion of one patient was made possible through access to the France Genomic Medicine Plan 2025 database.

  • Competing interests AC and MJT are employees of GeneDx, Inc. Other authors have no competing interests.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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