Exome sequencing and network analysis identifies shared mechanisms underlying spinocerebellar ataxia

Brain. 2017 Nov 1;140(11):2860-2878. doi: 10.1093/brain/awx251.


The autosomal dominant cerebellar ataxias, referred to as spinocerebellar ataxias in genetic nomenclature, are a rare group of progressive neurodegenerative disorders characterized by loss of balance and coordination. Despite the identification of numerous disease genes, a substantial number of cases still remain without a genetic diagnosis. Here, we report five novel spinocerebellar ataxia genes, FAT2, PLD3, KIF26B, EP300, and FAT1, identified through a combination of exome sequencing in genetically undiagnosed families and targeted resequencing of exome candidates in a cohort of singletons. We validated almost all genes genetically, assessed damaging effects of the gene variants in cell models and further consolidated a role for several of these genes in the aetiology of spinocerebellar ataxia through network analysis. Our work links spinocerebellar ataxia to alterations in synaptic transmission and transcription regulation, and identifies these as the main shared mechanisms underlying the genetically diverse spinocerebellar ataxia types.

Keywords: genetic network; neurodegeneration; spinocerebellar ataxia; synaptic transmission; whole exome sequencing.

MeSH terms

  • Animals
  • COS Cells
  • Cadherins / genetics
  • Chlorocebus aethiops
  • E1A-Associated p300 Protein / genetics
  • Exome / genetics
  • Female
  • Gene Regulatory Networks / genetics*
  • HEK293 Cells
  • Humans
  • Kinesin / genetics
  • Male
  • Pedigree
  • Phospholipase D / genetics
  • Plasmids
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Analysis, DNA
  • Spinocerebellar Ataxias / genetics*
  • Transfection


  • Cadherins
  • FAT1 protein, human
  • FAT2 protein, human
  • E1A-Associated p300 Protein
  • EP300 protein, human
  • Phospholipase D
  • phospholipase D3, human
  • KIF26B protein, human
  • Kinesin