Abstract for presentation at 11th International Congress of Human Genetics

Genetic variation of the T-type calcium channel gene CACNA1H in patients with idiopathic epilepsy

  • Ms Sarah Heron, Department of Genetic Medicine, Women’s and Children’s Hospital, North Adelaide, South Australia., Australia
  • Mr Houman Khosravani, Cellular and Molecular Neurobiology Research Group, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta., Canada
  • Mr Christopher Bladen, Cellular and Molecular Neurobiology Research Group, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta., Canada
  • Mr Diego Varela, Cellular and Molecular Neurobiology Research Group, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta., Canada
  • Ms Tristiana Williams, Department of Genetic Medicine, Women’s and Children’s Hospital, North Adelaide, South Australia., Australia
  • Ms Michelle Newman, Department of Genetic Medicine, Women’s and Children’s Hospital, North Adelaide, South Australia., Australia
  • Prof Samuel Berkovic, Department of Medicine (Neurology), The University of Melbourne and Austin Health, Heidelberg, Melbourne, Victoria., Australia
  • Prof Ingrid Scheffer, Department of Medicine (Neurology), The University of Melbourne and Austin Health, Royal Children's Hospital, Melbourne, Australia
  • Dr John Mulley, Department of Genetic Medicine, Women's and Children's Hospital, North Adelaide; Department of Molecular Biosciences, Universit, Australia
  • Prof Gerald Zamponi, Hotchkiss Brain Institute, Canada

    • The idiopathic epilepsies are thought to have a largely genetic basis, but genes of major effect have been identified in only a minority of families with epilepsy. Most cases of epilepsy are sporadic or occur in patients with only a few affected relatives. These cases are likely to have a polygenic or multifactorial basis, with variants in a number of genes as well as environmental factors contributing to the phenotype. Variants in the T-type calcium channel gene CACNA1H have been identified in patients with sporadic childhood absence epilepsy as well as a small number of families with other generalized epilepsies. Electrophysiological studies of these variants have shown changes in function consistent with the classification of CACNA1H as an epilepsy susceptibility gene.
    We screened a group of 240 (171 unrelated) patients with various epilepsy phenotypes for variants in CACNA1H using SSCA and identified a large number of novel variants, including 20 causing amino acid changes. Of these variants, 10 alter conserved amino acid residues. These changes were found in patients with epilepsy syndromes including febrile seizures, childhood absence epilepsy, juvenile absence epilepsy and myoclonic-astatic epilepsy. A proportion of these changes are likely to affect protein function and therefore contribute to complex epilepsy. These results show that CACNA1H exhibits considerable sequence variability, some of which contributes to the aetiology of the idiopathic epilepsies.

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