Mapping of a Gene Determining Familial Partial Epilepsy with Variable Foci to Chromosome 22q11-q12

Abstract

We identified two large French-Canadian families segregating a familial partial epilepsy syndrome with variable foci (FPEVF) characterized by mostly nocturnal seizures arising from frontal, temporal, and occasionally occipital epileptic foci. There is no evidence for structural brain damage or permanent neurological dysfunction. The syndrome is inherited as an autosomal dominant trait with incomplete penetrance. We mapped the disease locus to a 3. 8-cM interval on chromosome 22q11-q12, between markers D22S1144 and D22S685. Using the most conservative diagnostic scheme, the maximum cumulative LOD score was 6.53 at recombination fraction (straight theta) 0 with D22S689. The LOD score in the larger family was 5.34 at straight theta=0 with the same marker. The two families share an identical linked haplotype for >/=10 cM, including the candidate interval, indicating a recent founder effect. A severe phenotype in one of the probands may be caused by homozygosity for the causative mutation, as suggested by extensive homozygosity for the linked haplotype and a bilineal family history of epilepsy. An Australian family with a similar phenotype was not found to link to chromosome 22, indicating genetic heterogeneity of FPEVF.

Identification of Epilepsy Genes in Human and Mouse

“…Observed cosegregation of a spectrum of clinical features in a Mendelian inheritance pattern can provide the basis for defining a syndrome, as was done for GEFS+ (64), autosomal dominant partial epilepsy with auditory features (52), and familial partial epilepsy with variable foci (77). Alternatively, families can be selected for analysis based on the correspondence of the symptoms of affected family members with the defined clinical epilepsy syndromes (20).…”

Homozygosity mapping in a family presenting with schizophrenia, epilepsy and hearing impairment

“…Familial partial epilepsy syndrome with variable foci (FPEVF), an autosomal dominant and clinically heterogeneous condition, was initially mapped in two large French -Canadian pedigrees to a B4 Mb interval on chr 22q11-12. 22 Two preceding studies confirmed linkage for FPEVF in Dutch, Spanish and French-Canadian pedigrees reporting a combined LOD score of 6.3 for the Spanish and three French -Canadian pedigrees. 23,24 Of note, members of these pedigrees are reported to have psychiatric problems including the diagnosis of paranoid schizophrenia.…”

Genetic basis in epilepsies caused by malformations of cortical development and in those with structurally normal brain

“…Variable seizure severity between and within families is common. Structurally the brain appears normal Xiong et al 1999).…”

“…However in FPEVF seizures are less frequent, tend to occur in clusters, frequently accompanied by auras. More frequent day-time and secondarily generalized seizures are seen in FPEVF than in ADNFLE (Berkovic et al 2004b;Xiong et al 1999). Variable seizure severity between and within families is common.…”

“…Linkage was initially shown to chromosome 2q ), but other families have been linked to chromosome 22q (Berkovic et al 2004b;Callenbach et al 2003;Xiong et al 1999).…”