Identification of a novel in-frame de novo mutation in SPTAN1 in intellectual disability and pontocerebellar atrophy

Eur J Hum Genet. 2012 Jul;20(7):796-800. doi: 10.1038/ejhg.2011.271. Epub 2012 Jan 18.


Heterozygous in-frame mutations (p.E2207del and p.R2308_M2309dup) in the α-II subunit of spectrin (SPTAN1) were recently identified in two patients with intellectual disability (ID), infantile spasms (IS), hypomyelination, and brain atrophy. These mutations affected the C-terminal domain of the protein, which contains the nucleation site of the α/β spectrin heterodimer. By screening SPTAN1 in 95 patients with idiopathic ID, we found a de novo in-frame mutation (p.Q2202del) in the same C-terminal domain in a patient with mild generalized epilepsy and pontocerebellar atrophy, but without IS, hypomyelination, or other brain structural defects, allowing us to define the core phenotype associated with these C-terminal SPTAN1 mutations. We also found a de novo missense variant (p.R566P) of unclear clinical significance in a patient with non-syndromic ID. These two mutations induced different patterns of aggregation between spectrin subunits in transfected neuronal cell lines, providing a paradigm for the classification of candidate variants.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / diagnostic imaging
  • Brain / pathology
  • Carrier Proteins / genetics*
  • Case-Control Studies
  • Cell Line, Tumor
  • DNA Mutational Analysis / methods
  • Epilepsy / diagnosis
  • Epilepsy / genetics
  • Female
  • Fluorescent Antibody Technique / methods
  • Genetic Carrier Screening
  • Genetic Testing
  • Genome, Human
  • Heterozygote
  • Humans
  • Intellectual Disability / genetics*
  • Magnetic Resonance Imaging
  • Male
  • Mice
  • Microfilament Proteins / genetics*
  • Mutation, Missense
  • Olivopontocerebellar Atrophies / diagnosis
  • Olivopontocerebellar Atrophies / genetics*
  • Protein Structure, Tertiary
  • Radiography
  • Sequence Deletion*
  • Transfection


  • Carrier Proteins
  • Microfilament Proteins
  • fodrin