Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome

  • Nat Genet. 2021 Jul;53(7):1006-1021. doi: 10.1038/s41588-021-00886-z.
Margot A Cousin  #  1  2 ,  Blake A Creighton  #  3 ,  Keith A Breau  3 ,  Rebecca C Spillmann  4 ,  Erin Torti  5 ,  Sruthi Dontu  3 ,  Swarnendu Tripathi  6 ,  Deepa Ajit  3 ,  Reginald J Edwards  3 ,  Simone Afriyie  3 ,  Julia C Bay  3 ,  Kathryn M Harper  7  8 ,  Alvaro A Beltran  9  10 ,  Lorena J Munoz  10 ,  Liset Falcon Rodriguez  3 ,  Michael C Stankewich  11 ,  Richard E Person  5 ,  Yue Si  5 ,  Elizabeth A Normand  5 ,  Amy Blevins  5 ,  Alison S May  12 ,  Louise Bier  13 ,  Vimla Aggarwal  13  14 ,  Grazia M S Mancini  15 ,  Marjon A van Slegtenhorst  15 ,  Kirsten Cremer  16 ,  Jessica Becker  16 ,  Hartmut Engels  16 ,  Stefan Aretz  16 ,  Jennifer J MacKenzie  17 ,  Eva Brilstra  18 ,  Koen L I van Gassen  18 ,  Richard H van Jaarsveld  18 ,  Renske Oegema  18 ,  Gretchen M Parsons  19 ,  Paul Mark  19 ,  Ingo Helbig  20  21  22  23 ,  Sarah E McKeown  20  21 ,  Robert Stratton  24 ,  Benjamin Cogne  25  26 ,  Bertrand Isidor  25  26 ,  Pilar Cacheiro  27 ,  Damian Smedley  27 ,  Helen V Firth  28  29 ,  Tatjana Bierhals  30 ,  Katja Kloth  30 ,  Deike Weiss  31 ,  Cecilia Fairley  32 ,  Joseph T Shieh  32  33 ,  Amy Kritzer  34 ,  Parul Jayakar  35 ,  Evangeline Kurtz-Nelson  36 ,  Raphael A Bernier  36 ,  Tianyun Wang  37 ,  Evan E Eichler  37  38 ,  Ingrid M B H van de Laar  15 ,  Allyn McConkie-Rosell  4 ,  Marie T McDonald  4 ,  Jennifer Kemppainen  39  40 ,  Brendan C Lanpher  39  40 ,  Laura E Schultz-Rogers  39  41 ,  Lauren B Gunderson  39  40 ,  Pavel N Pichurin  39 ,  Grace Yoon  42 ,  Michael Zech  43  44 ,  Robert Jech  45 ,  Juliane Winkelmann  43  44  46  47 ,  Undiagnosed Diseases Network ,  Genomics England Research Consortium ,  Adriana S Beltran  10  48  49 ,  Michael T Zimmermann  6  50  51 ,  Brenda Temple  52 ,  Sheryl S Moy  7  8 ,  Eric W Klee  39  41  40 ,  Queenie K-G Tan  4 ,  Damaris N Lorenzo  53  54  55
Affiliations
  • 1. Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA. [email protected].
  • 2. Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA. [email protected].
  • 3. Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 4. Department of Pediatrics, Duke University Medical Center, Duke University, Durham, NC, USA.
  • 5. GeneDx, Gaithersburg, MD, USA.
  • 6. Bioinformatics Research and Development Laboratory, Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI, USA.
  • 7. Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 8. Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 9. Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 10. Human Pluripotent Stem Cell Core, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 11. Department of Pathology, Yale University, New Haven, CT, USA.
  • 12. Department of Neurology, Columbia University, New York, NY, USA.
  • 13. Institute for Genomic Medicine, Columbia University, New York, NY, USA.
  • 14. Laboratory of Personalized Genomic Medicine, Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
  • 15. Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
  • 16. Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
  • 17. McMaster University, Hamilton, Ontario, Canada.
  • 18. Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
  • 19. Spectrum Health Medical Genetics, Grand Rapids, MI, USA.
  • 20. Division of Neurology, Departments of Neurology and Pediatrics, The Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • 21. The Epilepsy NeuroGenetics Initiative, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 22. Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 23. Department of Neurology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
  • 24. Genetics, Driscoll Children's Hospital, Corpus Christi, TX, USA.
  • 25. Service de Génétique Médicale, CHU Nantes, Nantes, France.
  • 26. Université de Nantes, CNRS, INSERM, L'Institut du Thorax, Nantes, France.
  • 27. William Harvey Research Institute, School of Medicine and Dentistry, Queen Mary University of London, London, UK.
  • 28. Department of Clinical Genetics, Cambridge University Hospitals, Cambridge, UK.
  • 29. Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
  • 30. Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 31. Neuropediatrics, Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 32. Division of Medical Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
  • 33. Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.
  • 34. Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
  • 35. Nicklaus Children's Hospital, Miami, FL, USA.
  • 36. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
  • 37. Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.
  • 38. Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA.
  • 39. Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
  • 40. Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA.
  • 41. Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
  • 42. Divisions of Clinical/Metabolic Genetics and Neurology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
  • 43. Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.
  • 44. Institute of Human Genetics, Technical University of Munich, Munich, Germany.
  • 45. Department of Neurology, Charles University, 1st Faculty of Medicine and General University Hospital in Prague, Prague, Czech Republic.
  • 46. Lehrstuhl für Neurogenetik, Technische Universität München, Munich, Germany.
  • 47. Munich Cluster for Systems Neurology, SyNergy, Munich, Germany.
  • 48. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 49. Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 50. Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA.
  • 51. Clinical and Translational Sciences Institute, Medical College of Wisconsin, Milwaukee, WI, USA.
  • 52. Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 53. Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. [email protected].
  • 54. Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. [email protected].
  • 55. Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. [email protected].
  • # Contributed equally.
PMID: 34211179 DOI: 10.1038/s41588-021-00886-z
Abstract

SPTBN1 encodes βII-spectrin, the ubiquitously expressed β-spectrin that forms micrometer-scale networks associated with plasma membranes. Mice deficient in neuronal βII-spectrin have defects in cortical organization, developmental delay and behavioral deficiencies. These phenotypes, while less severe, are observed in haploinsufficient Animals, suggesting that individuals carrying heterozygous SPTBN1 variants may also show measurable compromise of neural development and function. Here we identify heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays; mild to severe intellectual disability; autistic features; seizures; behavioral and movement abnormalities; hypotonia; and variable dysmorphic facial features. We show that these SPTBN1 variants lead to effects that affect βII-spectrin stability, disrupt binding to key molecular partners, and disturb Cytoskeleton organization and dynamics. Our studies define SPTBN1 variants as the genetic basis of a neurodevelopmental syndrome, expand the set of spectrinopathies affecting the brain and underscore the critical role of βII-spectrin in the central nervous system.