DNA variants in coding region of EFHC1: SNPs do not associate with juvenile myoclonic epilepsy

Juvenile myoclonic epilepsy (JME) is the most common cause of primary grand mal seizures and accounts for at least 3 to 12% of all epilepsies. JME can be inherited as a Mendelian autosomal dominant or autosomal recessive trait or as a non-Mendelian complex genetic trait. Three mutation-harboring Mendelian genes for JME have been reported. Mutations in α1 subunit of γ-aminobutyric acid receptor subtype A on chromosome 5q34 segregated with nine affected individuals of a three-generation French Canadian family with JME (Cossette et al., 2002). Mutations in a chloride-channel gene, CLCN2 on chromosome 3q26 segregated with five affected members of a three-generation German family with JME (Haug et al., 2003). Our group first mapped a JME locus in chromosome 6p12 (Liu et al., 1995, 1996; Serratosa et al., 1996; Bai et al., 2002) and identified a mutation-harboring Mendelian gene that encodes a protein with one EF-hand motif. Hence, we called the gene EFHC1. We reported one doubly heterozygous and three heterozygous missense mutations segregated in 21 clinical and electroencephalography (EEG) affected members of six unrelated two- to four-generation JME Hispanic families from California (U.S.A.) and Mexico (Suzuki et al., 2004). The 6p12 JME locus was again mapped independently by two separate groups; first, by a genome-wide linkage study of JME families from various countries of Europe (Hempelmann et al., 2006) and second by a chromosome 6p12 replication genetic linkage study in a smaller cohort of 18 Dutch families (Pinto et al., 2004). Similar and novel missense mutations in EFHC1 were reported in Caucasian JME patients from Tennessee (U.S.A.), Italy, and Austria (Ma et al., 2006; Stogmann et al., 2006; Annesi et al., 2007). Therefore the causality of the gene in a Mendelian JME has been established, but the influence of common functional single nucleotide polymorphisms (SNPs) in JME with complex genetics has not been established. Pinto et al. (2006) reported three SNPs of EFHC1 that were not associated with JME in a case-control study of 112 unrelated patients and 180 controls. In our present study, we chose the most common four coding SNPs of EFHC1 and performed both case-control and family-based association studies to determine if they contribute to the complex genetics of JME.