Heterozygous missense variants of SPTBN2 are a frequent cause of congenital cerebellar ataxia

Clin Genet. 2019 Aug;96(2):169-175. doi: 10.1111/cge.13562. Epub 2019 Jun 5.


Heterozygous missense variants in the SPTBN2 gene, encoding the non-erythrocytic beta spectrin 2 subunit (beta-III spectrin), have been identified in autosomal dominant spinocerebellar ataxia type 5 (SCA5), a rare adult-onset neurodegenerative disorder characterized by progressive cerebellar ataxia, whereas homozygous loss of function variants in SPTBN2 have been associated with early onset cerebellar ataxia and global developmental delay (SCAR14). Recently, heterozygous SPTBN2 missense variants have been identified in a few patients with an early-onset ataxic phenotype. We report five patients with non-progressive congenital ataxia and psychomotor delay, 4/5 harboring novel heterozygous missense variants in SPTBN2 and one patient with compound heterozygous SPTBN2 variants. With an overall prevalence of 5% in our cohort of unrelated patients screened by targeted next-generation sequencing (NGS) for congenital or early-onset cerebellar ataxia, this study indicates that both dominant and recessive mutations of SPTBN2 together with CACNA1A and ITPR1, are a frequent cause of early-onset/congenital non-progressive ataxia and that their screening should be implemented in this subgroup of disorders.

Keywords: SCA5; SCAR14; SPTBN2; beta-III spectrin; congenital ataxia; spinocerebellar ataxia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Alleles
  • Amino Acid Sequence
  • Cerebellar Ataxia / diagnosis*
  • Cerebellar Ataxia / genetics*
  • Child
  • Child, Preschool
  • Computational Biology / methods
  • Genetic Association Studies*
  • Genetic Predisposition to Disease*
  • Heterozygote*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Infant
  • Models, Molecular
  • Mutation, Missense*
  • Pedigree
  • Phenotype
  • Spectrin / chemistry
  • Spectrin / genetics*


  • SPTBN2 protein, human
  • Spectrin