Evidence for digenic inheritance in a family with both febrile convulsionsand temporal lobe epilepsy implicating chromosomes 18qter and 1q25-q31

We report a clinical and genetic study of a French family among whom febril e convulsions (FC) are associated with subsequent temporal lobe epilepsy (T LE) in the same individual, without magnetic resonance imaging-identifiable hippocampal abnormalities. Linkage analyses excluded the loci FEB1 and FEB 2 previously implicated in FC; the GEFS+1 locus responsible for generalized epilepsy with febrile seizures plus; and the locus implicated in lateral t emporal lobe epilepsy. After scanning the entire genome, significant lod sc ores (>3) for markers on 18qter and suggestive lod scores (>2) for markers on 1q25-q31 were obtained. An analysis of the haplotypes at these two loci supported the hypothesis that two genes segregated with the phenotype. All patients shared common haplotypes for both 1q25-q31 and 18qter chromosomes. All but one unaffected at-risk individuals carried only one, or none, of t he disease haplotypes. Under the assumption of digenic inheritance, haploty pe reconstruction defined a 26 cM interval on chromosome 1 and a 10 cM inte rval on chromosome 18. This family suggests that the association between FC and TLE may be observed in the absence of hippocampal structural abnormali ties and that they may have, in some cases, a common genetic basis.