A locus for simple pure febrile seizures maps to chromosome 6q22-q24

Abstract

Febrile seizures (FS) syndromes exhibit major clinical and genetic heterogeneity. We report a clinical and genetic study of three families with simple FS segregating as an autosomal dominant (AD) trait with high penetrance. All affected members presented a homogeneous phenotype of simple FS. The FS ceased before the age of 5 years. Among the 29 affected family members, only one patient presented two afebrile seizures, and none of the others developed concomitant or subsequent epilepsy. The phenotype differs from that previously reported in families presenting FS or generalized epilepsy with febrile seizures plus (GEFS+). After exclusion of already known loci for FS and GEFS+, we performed a genome-wide scan in the largest family. It led to the identification of a new locus on chromosome 6q22-q24 spanning 6.4 cM between D6S1620 and D6S975. For one of the other two families, the trait also segregated with this locus, but linkage studies could not restrict the candidate region further. The absence of linkage in the third family supports genetic heterogeneity of the AD form of pure simple FS. Sequence analysis excluded the implication of five candidate genes [A kinase anchoring protein 18 (AKAP18), syntaxin 7, putative neurotransmitter receptor (PNR), G protein receptor 57 (GPR57) and G protein receptor 58 (GPR58)] in the interval based on function. The locus mapping to 6q22-q24 seems to be the first identified locus responsible for pure simple FS, the most frequent form of FS. Studies are ongoing to identify the gene.

Novel susceptibility locus at chromosome 6q16.3-22.31 in a family with GEFS+

“…Furthermore, the phenotype described in the 3 families with linkage to the FEB5 locus consists of simple FS with only 1 individual with later epilepsy. 23 Thus, we have no evidence to suggest that the relative proximity of our locus to FEB5 represents more than coincidence.…”

“…The nearest previously described locus is FEB5, spanning the region of 6q22.33-23.2 between microsatellite markers D6S1620 and D6S975. 23 As depicted schematically in figure 3, these regions are Results of linkage analysis using model-based and PPL methods (A) Two-point and multipoint lod scores from linkage analysis of microsatellite marker data using an autosomal dominant model with 90% penetrance, no sporadics, and 0.001 frequency of the susceptibility allele. The horizontal axis depicts the chromosome 6 microsatellite markers.…”

“…4,15 In addition, linkage studies have identified 7 genomic regions likely to harbor genes increasing risk for GEFSϩ and 5 regions likely to harbor genes increasing risk for FS (table 1). [16][17][18][19][20][21][22][23][24][25][26] Two loci originally described as FS loci (FEB3 and FEB4) were reported in pedigrees best classified as GEFSϩ due to phenotypes beyond typical FS. 20,21,27 Here we describe a GEFSϩ kindred from Central America with evidence for linkage to chromosome 6q16.…”

A hot topic

“…43 Mutations have been mapped to several chromosomal loci: FEB2 on chromosome 19p, FEB5 on chromosome 6q, FEB6 on chromosome 18p, FEB7 on chromosome 21q22, FEB9 on chromosome 3p24.2-p23 and FEB10 on 3q26. [44][45][46][47][48][49] Specific mutations to genes SCN1A and SCN9A encoding isoforms Na V 1.1 and Na V 1.7, respectively, have also been identified and associated with familial febrile convulsions. [50][51][52] Increased temperature sensitivity, either of the immature brain or due to mutations, is a likely mechanism of FS.…”

Genetic Epidemiology of Epilepsy or What Do We Tell Families?

“…Parental early age at onset of epilepsy also predicts risk to offspring. Parents (58) 2q23-24 FEB4 (59) 5q14-15 FEB5 (60) 6q22 -24 appear to be greater than that in the general population (4,6,7). In symptomatic epilepsy due to antenatal causes, the story is more complex, as some antenatal causes may be in part genetically modified, however, genetic risk is not substantial in most cases.…”