Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Cousin, MA; Creighton, BA; Breau, KA; Spillmann, RC; Torti, E; Dontu, S; Tripathi, S; Ajit, D; Edwards, RJ; Afriyie, S; Bay, JC; Harper, KM; Beltran, AA; Munoz, LJ; Falcon Rodriguez, L; Stankewich, MC; Person, RE; Si, Y; Normand, EA; Blevins, A; May, AS; Bier, L; Aggarwal, V; Mancini, GMS; van Slegtenhorst, MA; Cremer, K; Becker, J; Engels, H; Aretz, S; MacKenzie, JJ; Brilstra, E; van Gassen, KLI; van Jaarsveld, RH; Oegema, R; Parsons, GM; Mark, P; Helbig, I; McKeown, SE; Stratton, R; Cogne, B; Isidor, B; Cacheiro, P; Smedley, D; Firth, HV; Bierhals, T; Kloth, K; Weiss, D; Fairley, C; Shieh, JT; Kritzer, A; Jayakar, P; Kurtz-Nelson, E; Bernier, RA; Wang, T; Eichler, EE; van de Laar, IMBH; McConkie-Rosell, A; McDonald, MT; Kemppainen, J; Lanpher, BC; Schultz-Rogers, LE; Gunderson, LB; Pichurin, PN; Yoon, G; Zech, M; Jech, R; Winkelmann, J; Undiagnosed Diseases Network, ; Genomics England Research Consortium, ; Beltran, AS; Zimmermann, MT; Temple, B; Moy, SS; Klee, EW; Tan, QK-G; Lorenzo, DN

Published Date

  • July 2021

Published In

Volume / Issue

  • 53 / 7

Start / End Page

  • 1006 - 1021

PubMed ID

  • 34211179

Pubmed Central ID

  • PMC8273149

Electronic International Standard Serial Number (EISSN)

  • 1546-1718

Digital Object Identifier (DOI)

  • 10.1038/s41588-021-00886-z


  • eng

Conference Location

  • United States