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.

Bioinformatics Research and Development Laboratory Genomic Sciences and Precision Medicine Center Medical College of Wisconsin Milwaukee WI USA

Carolina Institute for Developmental Disabilities University of North Carolina at Chapel Hill Chapel Hill NC USA

Center for Individualized Medicine Mayo Clinic Rochester MN USA

Clinical and Translational Sciences Institute Medical College of Wisconsin Milwaukee WI USA

Department of Biochemistry and Biophysics University of North Carolina at Chapel Hill Chapel Hill NC USA

Department of Biochemistry Medical College of Wisconsin Milwaukee WI USA

Department of Biomedical and Health Informatics Children's Hospital of Philadelphia Philadelphia PA USA

Department of Cell Biology and Physiology University of North Carolina at Chapel Hill Chapel Hill NC USA

Department of Clinical Genetics Cambridge University Hospitals Cambridge UK

Department of Clinical Genetics Erasmus MC University Medical Center Rotterdam the Netherlands

Department of Clinical Genomics Mayo Clinic Rochester MN USA

Department of Genetics University Medical Center Utrecht Utrecht the Netherlands

Department of Genetics University of North Carolina at Chapel Hill Chapel Hill NC USA

Department of Genome Sciences University of Washington School of Medicine Seattle WA USA

Department of Neurology Charles University 1st Faculty of Medicine and General University Hospital Prague Prague Czech Republic

Department of Neurology Columbia University New York NY USA

Department of Neurology University of Pennsylvania Perelman School of Medicine Philadelphia PA USA

Department of Pathology Yale University New Haven CT USA

Department of Pediatrics Duke University Medical Center Duke University Durham NC USA

Department of Pharmacology University of North Carolina at Chapel Hill Chapel Hill NC USA

Department of Psychiatry and Behavioral Sciences University of Washington Seattle WA USA

Department of Psychiatry University of North Carolina at Chapel Hill Chapel Hill NC USA

Department of Quantitative Health Sciences Mayo Clinic Rochester MN USA

Division of Genetics and Genomics Boston Children's Hospital Boston MA USA

Division of Medical Genetics Department of Pediatrics University of California San Francisco San Francisco CA USA

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

Divisions of Clinical Metabolic Genetics and Neurology The Hospital for Sick Children University of Toronto Toronto Ontario Canada

GeneDx Gaithersburg MD USA

Genetics Driscoll Children's Hospital Corpus Christi TX USA

Howard Hughes Medical Institute University of Washington Seattle WA USA

Human Pluripotent Stem Cell Core University of North Carolina at Chapel Hill Chapel Hill NC USA

Institute for Genomic Medicine Columbia University New York NY USA

Institute for Human Genetics University of California San Francisco San Francisco CA USA

Institute of Human Genetics Technical University of Munich Munich Germany

Institute of Human Genetics University Medical Center Hamburg Eppendorf Hamburg Germany

Institute of Human Genetics University of Bonn School of Medicine and University Hospital Bonn Bonn Germany

Institute of Neurogenomics Helmholtz Zentrum München Munich Germany

Laboratory of Personalized Genomic Medicine Department of Pathology and Cell Biology Columbia University New York NY USA

Lehrstuhl für Neurogenetik Technische Universität München Munich Germany

McMaster University Hamilton Ontario Canada

Munich Cluster for Systems Neurology SyNergy Munich Germany

Neuropediatrics Department of Pediatrics University Medical Center Hamburg Eppendorf Hamburg Germany

Neuroscience Center University of North Carolina at Chapel Hill Chapel Hill NC USA

Nicklaus Children's Hospital Miami FL USA

Service de Génétique Médicale CHU Nantes Nantes France

Spectrum Health Medical Genetics Grand Rapids MI USA

The Epilepsy NeuroGenetics Initiative Children's Hospital of Philadelphia Philadelphia PA USA

Université de Nantes CNRS INSERM L'Institut du Thorax Nantes France

Wellcome Sanger Institute Wellcome Genome Campus Hinxton UK

William Harvey Research Institute School of Medicine and Dentistry Queen Mary University of London London UK

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