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Genes Linked to Rare Epilepsies Also Implicated in Common Epilepsies

NEW YORK (GenomeWeb) – Genes linked to rare forms of epilepsy also contribute to common types of the disease, according to a new study, suggesting that targeted treatments might be effective for some patients with common epilepsies.

In a case-control study, researchers from the Epi4K consortium and the Epilepsy Phenome/Genome Project sequenced the exomes of 640 individuals with familial genetic generalized epilepsy and 525 individuals with familial non-acquired focal epilepsy and compared them to sequences from 3,877 controls without epilepsy. As they reported last week in Lancet Neurology, the researchers found that people with these common forms of epilepsy had an enrichment of rare variants within genes previously linked to rare epilepsies.

"Our findings raise hopes that the emerging paradigm for the treatment of rare epilepsies, where therapies are targeted to the precise genetic cause of disease, may also extend to a proportion of common epilepsy syndromes," study leader David Goldstein from Columbia University Medical Center said in a statement.

In the familial genetic generalized epilepsy cohort, Goldstein and his colleagues uncovered 76,313 qualifying variants, or variants that could be pathogenic. While no single gene reached study-wide significance for enrichment of such variants, the top 10 case-enriched genes in this cohort included three known epilepsy genes: KCNQ2, GABRG2, and SCN1A.

Through their assessment of six biologically informed gene sets, the researchers found that the familial genetic generalized epilepsy cohort had a significant enrichment of ultra-rare — with a minor allele frequency of less than 0.05 percent — functional variation in 43 known dominant epilepsy genes and in a set of 33 genes associated with epileptic encephalopathy.

Similarly, the researchers reported that the familial non-acquired focal epilepsy cohort harbored 74,272 qualifying variants, though in this cohort, they found that DEPDC5 reached study-wide significance for enrichment of qualifying variants. In addition, Goldstein and his colleagues noted that the top five case-enriched genes in this cohort were all known epilepsy genes: DEPDC5, LGI1, PCDH19, SCN1A, and GRIN2A.

These five genes, they calculated, contribute to the risk of epilepsy in some 8 percent of people with familial non-acquired focal epilepsy, after correcting for background variation.

They likewise reported that both the known dominant epilepsy gene set and the epileptic encephalopathy gene set were enriched for qualifying variants among the familial non-acquired focal epilepsy cohort.

Their findings indicate that genes associated with familial and rare severe epilepsies are also associated with common forms of the disease.

For rare epilepsies, linking certain gene variants to disease has led to personalization of treatment approaches. For instance, patients with GLUT-1 deficiency syndrome, caused by mutations in SLC2A1, have been put on ketogenic diets, while children with other mutations have been given quinidine. With their findings, the researchers said, a similar personalization of treatment could be possible for more common forms of the disease.

"At present, all common epilepsies are treated the same way, with the same group of medications," Goldstein said. "But as we identify more of these epilepsy genes that span a much wider range of types of epilepsy than previously thought, we can begin to try targeted therapies across these patient populations."