Genetic testing in epilepsy -- it takes more than 1 gene

Imagine two flat screen televisions tuned to the same channel and sitting side-by-side. From a distance, their pictures are virtually the same, however up close, you can see subtle variations in the pixels – one blurred here, another dropped out there.

Suppose some of these 'bad pixels' are known to produce periodic black-out spells on the screen. Would a sharper image revealing all of the defects help identify which of the screens works perfectly, and which one needs repair?

Seven years ago, Dr. Jeffrey Noebels , professor of neurology, neuroscience and molecular and human genetics at Baylor College of Medicine, (www.bcm.edu) and Dr. Richard Gibbs, director of the Baylor Human Genome Sequencing Center (http://www.hgsc.bcm.tmc.edu/), began the first large-scale sequencing project to survey nearly all the genes encoding ion channels, the electrical 'pixels' of the brain.

These channels are the tiny pores that allow molecules of sodium, calcium, potassium, and chloride to move in and out of the cell, creating the electrical impulses that drive signaling within brain networks. A disruption of the signaling pattern leads to epilepsy, a common severe neurological disorder.

Because the causes of most epilepsies remain mysterious, they hoped to identify specific "pixels" that might predict who will have seizures. Hundreds of subjects and terabytes of data later, Noebels, Gibbs and their colleagues at BCM found dozens of individually rare variants in the epilepsy-related ion channel genes in people who had epilepsy, and intriguingly, nearly just as many in those who did not. Why are some individuals more fortunate?

Analyzing those personal variations and how they contribute to a large picture is part of the next step in understanding unexplained epilepsy – and many other disorders linked to ion channel diseases throughout the body – including the brain, eye, ear, heart, muscle, kidney and pancreas. Typically, when a known disease gene is uncovered, a patient is told he or she is at risk for the condition. However, a better answer may lie in the patterns of all the defective channels rather than any single one of them.

"We are all born with a few erratic pixels, but luckily they do not always add up to disease. It takes a village," said Noebels, who is also director of the Blue Bird Circle Developmental Neurogenetics Laboratory at BCM and a pioneer in genetic epilepsy research. A report on the work appears in the current issue of the journal Cell.

"We began looking at ion channels because they are the largest class of genes that contribute to seizures. In some families, even a single defective one is a master switch for epilepsy," said Noebels. "But we soon realized that small defects in other channels could aggravate the problem in some individuals, or mask it in others. Instead of looking at one incriminating gene at a time and pronouncing it guilty, as is often done in single gene testing, we wanted to step back and examine them all."