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Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome
MA. Cousin, BA. Creighton, KA. Breau, RC. Spillmann, E. Torti, S. Dontu, S. Tripathi, D. Ajit, RJ. Edwards, S. Afriyie, JC. Bay, KM. Harper, AA. Beltran, LJ. Munoz, L. Falcon Rodriguez, MC. Stankewich, RE. Person, Y. Si, EA. Normand, A. Blevins,...
Language English Country United States
Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
Grant support
P30 NS045892
NINDS NIH HHS - United States
U01 HG007672
NHGRI NIH HHS - United States
U54 HD079124
NICHD NIH HHS - United States
R01 NS110810
NINDS NIH HHS - United States
Wellcome Trust - United Kingdom
R01 MH101221
NIMH NIH HHS - United States
Department of Health - United Kingdom
Cancer Research UK - United Kingdom
Medical Research Council - United Kingdom
Howard Hughes Medical Institute - United States
NLK
ProQuest Central
from 2000-01-01 to 1 year ago
Health & Medicine (ProQuest)
from 2000-01-01 to 1 year ago
Public Health Database (ProQuest)
from 2000-01-01 to 1 year ago
- MeSH
- Genes, Dominant * MeSH
- Phenotype MeSH
- Genetic Predisposition to Disease * MeSH
- Genetic Variation * MeSH
- Genetic Association Studies methods MeSH
- Heterozygote MeSH
- Humans MeSH
- Mice MeSH
- Neurodevelopmental Disorders diagnosis genetics MeSH
- Spectrin genetics metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
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.
Center for Individualized Medicine Mayo Clinic Rochester MN USA
Clinical and Translational Sciences Institute Medical College of Wisconsin Milwaukee WI USA
Department of Biochemistry Medical College of Wisconsin Milwaukee WI 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 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
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 Neurogenomics Helmholtz Zentrum München Munich Germany
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
References provided by Crossref.org
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- $a Cousin, Margot A $u Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA. cousin.margot@mayo.edu $u Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA. cousin.margot@mayo.edu
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- $a Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome / $c MA. Cousin, BA. Creighton, KA. Breau, RC. Spillmann, E. Torti, S. Dontu, S. Tripathi, D. Ajit, RJ. Edwards, S. Afriyie, JC. Bay, KM. Harper, AA. Beltran, LJ. Munoz, L. Falcon Rodriguez, MC. Stankewich, RE. Person, Y. Si, EA. Normand, A. Blevins, AS. May, L. Bier, V. Aggarwal, GMS. Mancini, MA. van Slegtenhorst, K. Cremer, J. Becker, H. Engels, S. Aretz, JJ. MacKenzie, E. Brilstra, KLI. van Gassen, RH. van Jaarsveld, R. Oegema, GM. Parsons, P. Mark, I. Helbig, SE. McKeown, R. Stratton, B. Cogne, B. Isidor, P. Cacheiro, D. Smedley, HV. Firth, T. Bierhals, K. Kloth, D. Weiss, C. Fairley, JT. Shieh, A. Kritzer, P. Jayakar, E. Kurtz-Nelson, RA. Bernier, T. Wang, EE. Eichler, IMBH. van de Laar, A. McConkie-Rosell, MT. McDonald, J. Kemppainen, BC. Lanpher, LE. Schultz-Rogers, LB. Gunderson, PN. Pichurin, G. Yoon, M. Zech, R. Jech, J. Winkelmann, Undiagnosed Diseases Network, Genomics England Research Consortium, AS. Beltran, MT. Zimmermann, B. Temple, SS. Moy, EW. Klee, QK. Tan, DN. Lorenzo
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