Researchers search for possible biologic mechanisms that may account for the co-occurrence of autism and epilepsy.
SAN ANTONIO—Testing genes with biologic relevance to epilepsy yielded a significant association to a pair of single nucleotide polymorphisms (SNPs) in a gene recently implicated in autism as well as idiopathic generalized epilepsy, according to research presented at the 64th Annual Meeting of the American Epilepsy Society.
The two SNPs—rs11079919 and rs9898731—were identified in the calcium channel gene CACNA1G, although additional SNPs of interest were observed as well, reported Michael L. Cuccaro, PhD, Associate Professor, Department of Human Genetics, University of Miami School of Medicine, and colleagues.
“The role of ion channel genes in autism risk is supported by evidence showing that calcium channel dysfunction is tied to both syndromic and nonsyndromic autism,” stated the researchers. “For example, Timothy syndrome, a multisystem disorder characterized by cardiac, immune, and cognitive abnormalities, along with a clearly defined autism phenotype, results from a CACNA1C mutation.”
Dr. Cuccaro’s group tested 20 candidate genes in a discovery dataset of 438 autism families and in a validation subset of 457 autism families. SNPs were tested with use of the Pedigree Disequilibrium Test, and gene-based corrections for multiple tests were applied by adjusting significance levels by the number of available markers in each gene. The investigators regarded a finding as significant if a marker was nominally significant in the datasets and met corrected significance in the joint analyses.
The two SNPs—rs11079919 and rs9898731—that were significant in the autism families are located in CACNA1G regions. The investigators also included two SNPs—rs757415 and rs12603112—from another study in their analysis.
None of the four SNPs of interest in CACNA1G was significant in the initial autism-epilepsy subset (n = 43), according to the researchers. “Stratifying on autism-epilepsy in 43 families, we identified 75 nominally significant results, about 2,200 markers,” they noted. “We then examined these markers in an expanded autism-epilepsy dataset, in 71 families. Three SNPs showed a greater signal when they were examined in the larger dataset.
“Calcium-dependent defects that perturb neural development lead to changes common to those found in autism—for example, cell-packing density, decreases in neuron size and arborization, and alterations in connectivity,” the researchers concluded. “Further, calcium channel variants in autism—for example, CACNA1G—are tied to increased signaling, suggesting a role for calcium-dependent activation in this disorder.”
—Colby Stong