A new EF-hand containing gene EFHC2 on Xp11.4: Tentative evidence for association with juvenile myoclonic epilepsy

Genetic factors play a major role in the etiology of idiopathic generalized epilepsies (IGE). An oligogenic or polygenic predisposition is suspected in the majority of families with common IGE syndromes. It has been hypothesized that some IGE genes might increase the general level of neuronal excitability while others specify the age of onset and the seizure type. The EFHC1 gene on 6p12-p11 was previously described as the first susceptibility gene for juvenile myoclonic epilepsy (JME). EFHC1 codes for a protein of unknown function that is characterized by Ca2+-binding EF-hand motifs and DM10 domains. We have now cloned the brain-expressed paralog EFHC2 (Xp11.3) and carried out an association study of six single nucleotide polymorphisms (SNPs) in a large sample of 654 German IGE patients and 662 population controls. A tentative association was found between the amino acid exchange S430Y in exon 9 of EFHC2 and 97 male JME patients (χ2  =  4.705, d.f. = 1, P = 0.030; OR = 2.17; 95-CI: 1.06-4.43). The allelic association was even stronger for the 81 males with “classical” JME (JME without absence seizures) (χ2 = 6.06, d.f. = 1, P = 0.014; OR = 2.46; 95-CI: 1.18-5.13). An association with the gonosomal gene EFHC2 would be in accordance with the observed preponderance of maternal inheritance in JME maternal inheritance of JME. Independent replication studies are needed to further analyse the tentative association described here.