Phenytoin and carbamazepine are effective and inexpensive antiepileptic drugs (AEDs). As with many AEDs, a broad range of doses is used, with the final ''maintenance'' dose normally determined by trial and error. Although many genes could influence response to these medicines, there are obvious candidates. Both drugs target the ␣-subunit of the sodium channel, encoded by the SCN family of genes. Phenytoin is principally metabolized by CYP2C9, and both are probable substrates of the drug transporter P-glycoprotein. We therefore assessed whether variation in these genes associates with the clinical use of carbamazepine and phenytoin in cohorts of 425 and 281 patients, respectively. We report that a known functional polymorphism in CYP2C9 is highly associated with the maximum dose of phenytoin (P ‫؍‬ 0.0066). We also show that an intronic polymorphism in the SCN1A gene shows significant association with maximum doses in regular usage of both carbamazepine and phenytoin (P ‫؍‬ 0.0051 and P ‫؍‬ 0.014, respectively). This polymorphism disrupts the consensus sequence of the 5 splice donor site of a highly conserved alternative exon (5N), and it significantly affects the proportions of the alternative transcripts in individuals with a history of epilepsy. These results provide evidence of a drug target polymorphism associated with the clinical use of AEDs and set the stage for a prospective evaluation of how pharmacogenetic diagnostics can be used to improve dosing decisions in the use of phenytoin and carbamazepine. Although the case made here is compelling, our results cannot be considered definitive or ready for clinical application until they are confirmed by independent replication. association study ͉ epilepsy ͉ pharmacogenetics P henytoin and carbamazepine are important first-line antiepileptic drugs (AEDs) and are widely prescribed throughout the world. Control of epilepsy with phenytoin can be a difficult and lengthy process because of the drug's narrow therapeutic index and the wide interindividual range of doses required. Similarly, appropriate doses for carbamazepine take time to determine because of autoinduction of metabolism and neurologic side effects generally assumed to necessitate slow dose increases. Adverse drug reactions (ADRs) are relatively common for both drugs.Phenytoin is metabolized by the hepatic cytochrome P450 enzymes CYP2C9 and CYP2C19, is transported by Pglycoprotein, and targets the ␣-subunit of the sodium channel.

Deletions at 16p13.11 are associated with schizophrenia, mental retardation, and most recently idiopathic generalized epilepsy. To evaluate the role of 16p13.11 deletions, as well as other structural variation, in epilepsy disorders, we used genome-wide screens to identify copy number variation in 3812 patients with a diverse spectrum of epilepsy syndromes and in 1299 neurologically-normal controls. Large deletions (> 100 kb) at 16p13.11 were observed in 23 patients, whereas no control had a deletion greater than 16 kb. Patients, even those with identically sized 16p13.11 deletions, presented with highly variable epilepsy phenotypes. For a subset of patients with a 16p13.11 deletion, we show a consistent reduction of expression for included genes, suggesting that haploinsufficiency might contribute to pathogenicity. We also investigated another possible mechanism of pathogenicity by using hybridization-based capture and next-generation sequencing of the homologous chromosome for ten 16p13.11-deletion patients to look for unmasked recessive mutations. Follow-up genotyping of suggestive polymorphisms failed to identify any convincing recessive-acting mutations in the homologous interval corresponding to the deletion. The observation that two of the 16p13.11 deletions were larger than 2 Mb in size led us to screen for other large deletions. We found 12 additional genomic regions harboring deletions > 2 Mb in epilepsy patients, and none in controls. Additional evaluation is needed to characterize the role of these exceedingly large, non-locus-specific deletions in epilepsy. Collectively, these data implicate 16p13.11 and possibly other large deletions as risk factors for a wide range of epilepsy disorders, and they appear to point toward haploinsufficiency as a contributor to the pathogenicity of deletions.

Most people in the developed world will sooner or later be given prescription drugs to treat common diseases or to reduce the risk of getting them. Almost everyone who takes medicines will, at some stage, encounter those that do not work as well as they do in other people or even that cause an adverse reaction. Pharmacogenetics seeks to reduce the variation in how people respond to medicines by tailoring therapy to individual genetic make-up. It seems increasingly likely that investment in this field might be the most effective strategy for rapidly delivering the public health benefits that are promised by the Human Genome Project and related endeavours.