Suggestion of a major gene for familial febrile convulsions mapping to 8q13-21.

Abstract

Febrile convulsions affect 2 to 5% of all children under the age of 5 years. These convulsions probably have a variety of causes, but a genetic component has long been recognised. A large and remarkable family is described in which febrile convulsions appear to result from autosomal dominant inheritance at a single major locus. A gene for febrile convulsions was excluded from regions of previously mapped epilepsy genes and extension of exclusion mapping, using microsatellite markers, to the entire genome implied that a locus on chromosome 8q13-21 may be involved. Linkage analysis of markers on chromosome 8 gave a multipoint lod score of 3 40, maximised over different values of penetrance and phenocopy rate, for linkage between the gene for febrile convulsions and the region flanked by markers D8S553 and D8S279. This lod score was calculated assuming the disease has a penetrance of 60% and a phenocopy rate of 3%. Although there was no indication of linkage other than to markers on chromosome 8, linkage remains suggestive rather than significant because ofthe maximisation procedure applied. The support for linkage involving a major gene, as opposed to an alternative hypothesis of a complex inheritance pattern, relied upon the assumption of low penetrance. (J Med Genet 1996;33:308-312)

A missense mutation of the Na + channel α II subunit gene Na v 1.2 in a patient with febrile and afebrile seizures causes channel dysfunction

“…Because the febrile seizure is the most commonly provoked seizure afflicting infants and children, it is likely that numerous factors contribute to generate heterogeneous seizure phenotypes. Actually, several loci are known to be responsible for FS (5)(6)(7)(8)(9). The febrile seizures of mother and maternal aunt may therefore most probably be accounted for by defects in other genes.…”

“…Extensive genetic studies have demonstrated that four loci are responsible for FS: FEB1 at chromosome 8q13-q21; FEB2, 19p; FEB3, 2q23-24; and FEB4, 5q14-q15 (5)(6)(7)(8)(9). A small population of individuals with FS has additional generalized epilepsy (1) or afebrile seizures.…”

Identification of an Na v 1.1 sodium channel (SCN1A) loss-of-function mutation associated with familial simple febrile seizures

“…Of these patients, two had a MRI-evidenced MTS, but only one (IV-3) showed FS lasting up to 15 min, indicating a putative example of complex FS. The association between familial AD FS and MTLE has already been proposed in large pedigrees, suggesting a common genetic basis whether MTS is present or not (2,15). In particular, it has been shown that a family history of simple FS also can be a risk factor for MTLE (16).…”

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

“…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.…”