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 present with measurable compromise of neural development and function. Here we identify heterozygous SPTBN1 variants in 29 individuals who present 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 βIIspectrin 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. Spectrins are ubiquitously expressed, elongated polypeptides that bind membrane lipids and ankyrins to line the plasma membrane 1,2 . The spectrin meshwork is formed by heterodimeric units of α-spectrin and β-spectrin assembled side-to-side in antiparallel fashion, which then form head-to-head tetramers that crosslink F-actin to form spectrin-actin arrays 1,2 . Mammalian neurons express the most diverse repertoire of spectrins, which Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms *