Heterozygous variants in SPTBN1 cause intellectual disability and autism

Am J Med Genet A. 2021 Jul;185(7):2037-2045. doi: 10.1002/ajmg.a.62201. Epub 2021 Apr 13.


Spectrins are common components of cytoskeletons, binding to cytoskeletal elements and the plasma membrane, allowing proper localization of essential membrane proteins, signal transduction, and cellular scaffolding. Spectrins are assembled from α and β subunits, encoded by SPTA1 and SPTAN1 (α) and SPTB, SPTBN1, SPTBN2, SPTBN4, and SPTBN5 (β). Pathogenic variants in various spectrin genes are associated with erythroid cell disorders (SPTA1, SPTB) and neurologic disorders (SPTAN1, SPTBN2, and SPTBN4), but no phenotypes have been definitively associated with variants in SPTBN1 or SPTBN5. Through exome sequencing and case matching, we identified seven unrelated individuals with heterozygous SPTBN1 variants: two with de novo missense variants and five with predicted loss-of-function variants (found to be de novo in two, while one was inherited from a mother with a history of learning disabilities). Common features include global developmental delays, intellectual disability, and behavioral disturbances. Autistic features (4/6) and epilepsy (2/7) or abnormal electroencephalogram without overt seizures (1/7) were present in a subset. Identification of loss-of-function variants suggests a haploinsufficiency mechanism, but additional functional studies are required to fully elucidate disease pathogenesis. Our findings support the essential roles of SPTBN1 in human neurodevelopment and expand the knowledge of human spectrinopathy disorders.

Keywords: SPTBN1; neurodevelopmental disorder; spectrin; spectrinopathy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Autistic Disorder / diagnostic imaging
  • Autistic Disorder / genetics*
  • Autistic Disorder / pathology
  • Carrier Proteins / genetics
  • Child
  • Child, Preschool
  • Electroencephalography
  • Epilepsy / diagnostic imaging
  • Epilepsy / genetics*
  • Epilepsy / pathology
  • Female
  • Haploinsufficiency / genetics
  • Heterozygote
  • Humans
  • Intellectual Disability / diagnostic imaging
  • Intellectual Disability / genetics*
  • Intellectual Disability / pathology
  • Loss of Function Mutation / genetics
  • Male
  • Microfilament Proteins / genetics
  • Phenotype
  • Problem Behavior
  • Seizures / diagnostic imaging
  • Seizures / genetics*
  • Seizures / pathology
  • Spectrin / genetics*
  • Whole Exome Sequencing
  • Young Adult


  • Carrier Proteins
  • Microfilament Proteins
  • SPTBN1 protein, human
  • SPTBN2 protein, human
  • fodrin
  • Spectrin