(From the June 2015 issue of Research Now)
Juvenile myoclonic epilepsy (JME) is a common form of epilepsy that is idiopathic, or of unknown cause, and is thought to require life-long medication to suppress seizures. The condition generally starts in adolescence, usually between the ages of 8 and 20 years, and lasts into adulthood. Previous studies have reported that mutations in the EFHC1 gene are the cause of as much as 9 percent of all cases of JME.
However, in a study recently published in the journal Epilepsia, researchers from Nationwide Children’s Hospital analyzed genetic data from multiple populations, including understudied Hispanic and black/African American ethnicities, and found that the specific mutations in the EFHC1 gene that were previously reported to cause JME varied in frequency, depending on ethnicity. In fact, these specific mutations were quite common in some populations, casting doubt on EFHC1’s contribution as a cause of JME.
David Greenberg, PhD, is senior author of the new study, which was coauthored by William Stewart, PhD. Both are principal investigators in the Battelle Center for Mathematical Medicine in The Research Institute at Nationwide Children’s.
According to Dr. Greenberg, previous research published by Suzuki et al. in 2004 presented evidence that mutations in the gene EFHC1 caused – and were not merely associated with – JME in a Hispanic population. Specifically, Suzuki’s team conducted a linkage analysis of 45 families that identified a JME-linked region on chromosome 6p12. Upon sequencing the exons of several genes in the region, three different mutations were found in EFHC1, but only in 5 of the 45 families. These same mutations were not found in 300 Mexican controls.
“Much of the current literature accepts that EFHC1 mutations are a major cause of JME in Hispanics,” says Dr. Greenberg, who is also the director of Neurogenetics for the Battelle Center for Mathematical Medicine and the Department of Neurology at Nationwide Children’s. “However, what we wanted to know is, if the mutations in EFHC1 exons cause JME in this population, why were no mutations found in the sequenced exons of the other 40 JME families who were part of the Suzuki study?”
Therefore, Drs. Greenberg and Stewart, along with colleagues, analyzed the frequency of EFHC1 exonic mutations in African American and Hispanic JME patients and controls. They also examined data from the 1000 Genomes Project, which included human genome sequences from around the world.
“We found that, in our sample of black and Hispanic patients and controls, the mutations described as ‘causative’ by Suzuki et al. were just as common in matched controls as in cases,” says Dr. Greenberg. “Furthermore, the frequency of those ‘mutations’ were quite high – up to 8 percent – in some reference populations, such as Sardinians and West Africans, according to the 1000 Genomes data.”
Results from this study demonstrated that the frequencies of those EFHC1 exonic mutations were far higher than even the frequency of all the epilepsies combined, not just JME.
“This linkage result shows thereis a gene in the 6p12 region that strongly influences JME in some patients in some populations, such as Hispanics,” says Dr. Greenberg, who is also a professor of Pediatrics at The Ohio State University College of Medicine. “But the claim that EFHC1 is the gene, based on the observations of a few exonic mutations by past researchers, is hasty at best.”
Other researchers who conducted studies after the Suzuki paper also showed there was no association of JME with markers in the region in the Mexican sample used by Suzuki and team. Associations might have been expected had the disease in fact been caused by a small number of mutations.
Although it is still possible that EFHC1 is a cause of JME in the Hispanic population examined by Suzuki et al., the mutations identified in EFHC1 cannot be “causative” as they exist in normal populations at levels as high or higher as is seen in JME patients, according to Dr. Greenberg and colleagues. There may be variants in non-coding portions of the gene, but these will require much more work to identify. And scientists currently do not know how to identify disease-causing variants in the non-coding genome.
“The most parsimonious explanation is that there is some other gene in the linkage-identified region that is involved in the disease,” concludes Dr. Greenberg. “Our study shows that simply knowing gene sequences, without understanding the roles of ethnic differences, population genetics, linkage and association analysis, will more often lead us down wrong paths, even in the face of sophisticated molecular biology.”
Subaran RL, Conte JM, Stewart WCL, Greenberg DA. Pathogenic EFHC1 mutations are tolerated in healthy individuals dependent on reported ancestry. Epilepsia. 2015 Feb;56(2):188-194.