Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome

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 sever...

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Published in:	Nature genetics Vol. 53; no. 7; pp. 1006 - 1021
Main Authors:	Cousin, Margot A., Creighton, Blake A., Breau, Keith A., Spillmann, Rebecca C., Torti, Erin, Dontu, Sruthi, Tripathi, Swarnendu, Ajit, Deepa, Edwards, Reginald J., Afriyie, Simone, Bay, Julia C., Harper, Kathryn M., Beltran, Alvaro A., Munoz, Lorena J., Falcon Rodriguez, Liset, Stankewich, Michael C., Person, Richard E., Si, Yue, Normand, Elizabeth A., Blevins, Amy, May, Alison S., Bier, Louise, Aggarwal, Vimla, Mancini, Grazia M. S., van Slegtenhorst, Marjon A., Cremer, Kirsten, Becker, Jessica, Engels, Hartmut, Aretz, Stefan, MacKenzie, Jennifer J., Brilstra, Eva, van Gassen, Koen L. I., van Jaarsveld, Richard H., Oegema, Renske, Parsons, Gretchen M., Mark, Paul, Helbig, Ingo, McKeown, Sarah E., Stratton, Robert, Cogne, Benjamin, Isidor, Bertrand, Cacheiro, Pilar, Smedley, Damian, Firth, Helen V., Bierhals, Tatjana, Kloth, Katja, Weiss, Deike, Fairley, Cecilia, Shieh, Joseph T., Kritzer, Amy, Jayakar, Parul, Kurtz-Nelson, Evangeline, Bernier, Raphael A., Wang, Tianyun, Eichler, Evan E., van de Laar, Ingrid M. B. H., McConkie-Rosell, Allyn, McDonald, Marie T., Kemppainen, Jennifer, Lanpher, Brendan C., Schultz-Rogers, Laura E., Gunderson, Lauren B., Pichurin, Pavel N., Yoon, Grace, Zech, Michael, Jech, Robert, Winkelmann, Juliane, Beltran, Adriana S., Zimmermann, Michael T., Temple, Brenda, Moy, Sheryl S., Klee, Eric W., Tan, Queenie K.-G., Lorenzo, Damaris N.
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01-07-2021 Nature Publishing Group
Subjects:	631/208/366/1373 692/699/375/366/1311 Abnormalities Agriculture Animal Genetics and Genomics Animals Ataxia Autism Biomedical and Life Sciences Biomedicine Cancer Research Causes of Central nervous system Child development deviations Convulsions & seizures Cytoskeletal proteins Cytoskeleton Developmental disabilities Gene Function Gene mutations Genes, Dominant Genetic aspects Genetic Association Studies - methods Genetic disorders Genetic Predisposition to Disease Genetic research Genetic Variation Genotype & phenotype Health aspects Heterozygote Human Genetics Humans Hypotonia Intellectual disabilities Magnetic resonance imaging Mice Nervous system Nervous system diseases Neurodevelopmental disorders Neurodevelopmental Disorders - diagnosis Neurodevelopmental Disorders - genetics Phenotype Phenotypes Plasma membranes Proteins Seizures Siblings Spectrin Spectrin - genetics Spectrin - metabolism Structure United States
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Summary:	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. SPTBN1 mutations cause a neurodevelopmental syndrome characterized by intellectual disability, language and motor delays, autism, seizures and other features. The variants disrupt βII-spectrin function and disturb cytoskeletal organization and dynamics.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Consortia Undiagnosed Diseases Network M.A.C. and D.N.L. conceived and planned the study with input from Q.K.-G.T and R.C.S. M.A.C. managed the collection, analysis, and interpretation of patient clinical data with Q.K.-G.T., R.C.S., and D.N.L. D.N.L. designed the cell biology, histology, and biochemistry studies, performed these and analyzed the data together with B.A.C., K.A.B., S.D., D.A., R.J.E., S.A., J.C.B., and L.F.R. A.A.B., L.J.M., and A.S.B. generated and characterized the iPSCs. S.T., M.T.Z., B.T. and D.N.L. performed the structural modeling. K.M.H. and S.S.M. performed the mouse behavioral studies. M.C.S. contributed reagents. M.A.C. and D.N.L. wrote the manuscript with contributions from B.A.C., R.C.S., S.S.M., M.T.Z., and B.T. E.W.K. and D.N.L. supervised the study. All other authors including Q.K.-G.T. and R.C.S. contributed clinical data. All authors approved the final manuscript. Rebecca C. Spillmann4, Allyn McConkie-Rosell4, Brendan C. Lanpher1,39, and Queenie K.-G. Tan4 A full list of consortium members appears in the Supplementary Note. Genomics England Research Consortium Author Contributions Damian Smedley27
ISSN:	1061-4036 1546-1718 1546-1718
DOI:	10.1038/s41588-021-00886-z