Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome

Genomics England Research Consortium, Margot A. Cousin*, Undiagnosed Diseases Network, Blake A. Creighton, Keith A. Breau, Rebecca C. Spillmann, Erin Torti, Sruthi Dontu, Swarnendu Tripathi, Deepa Ajit, Reginald J. Edwards, Simone Afriyie, Julia C. Bay, Kathryn M. Harper, Alvaro A. Beltran, Lorena J. Munoz, Liset Falcon Rodriguez, Michael C. Stankewich, Richard E. Person, Yue SiElizabeth A. Normand, Amy Blevins, Alison S. May, Louise Bier, Vimla Aggarwal, Grazia M.S. Mancini, Marjon A. van Slegtenhorst, Kirsten Cremer, Jessica Becker, Hartmut Engels, Stefan Aretz, Jennifer J. MacKenzie, Eva Brilstra, Koen L.I. van Gassen, Richard H. van Jaarsveld, Renske Oegema, Gretchen M. Parsons, Paul Mark, Ingo Helbig, Sarah E. McKeown, Robert Stratton, Benjamin Cogne, Bertrand Isidor, Pilar Cacheiro, Damian Smedley, Helen V. Firth, Tatjana Bierhals, Katja Kloth, Deike Weiss, Cecilia Fairley, Joseph T. Shieh, Ingrid M.B.H. van de Laar, Q Tan, Damaris Lorenzo

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

26 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1006-1021
Number of pages16
JournalNature Genetics
Issue number7
Publication statusPublished - 1 Jul 2021

Bibliographical note

Funding Information:
We thank all the families who participated in this study. We thank M. Rasband and K.-A. Nave for the gift of the βII-spectrin conditional null and the Nex-Cre mice, respectively. We thank N. V. Riddick for her assistance with the behavioral studies. We thank B. Koller and K. Mohlke for their insightful comments on this manuscript and J. Bear for helpful discussions. M.A.C., L.E.S.-R. and E.W.K. were supported by the Center for Individualized Medicine at the Mayo Clinic. D.N.L. was supported by the University of North Carolina at Chapel Hill (UNC-CH) School of Medicine as a Simmons Scholar, by the National Ataxia Foundation and by the US National Institutes of Health (NIH) grant no. R01NS110810. E.E.E. was supported by the NIH grant no. MH101221. Microscopy was performed at the UNC-CH Neuroscience Microscopy Core Facility, supported, in part, by funding from the NIH-NINDS Neuroscience Center Grant no. P30 NS045892 and the NIH-NICHD Intellectual and Developmental Disabilities Research Center Support Grant no. U54 HD079124, which also supported the behavioral studies. Research reported in this manuscript was supported by the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director under Award Number U01HG007672 (Duke University to V. Shashi). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support.

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.


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