2. Academic Validation
  3. Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome

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

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.

Figures