Alternative titles; symbols
HGNC Approved Gene Symbol: FEB1
DO: 0111307;
Cytogenetic location: 8q13-q21 Genomic coordinates (GRCh38) : 8:65,100,001-92,300,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q13-q21 | Febrile seizures, familial, 1 | 121210 | Autosomal dominant | 2 |
Childhood seizures associated with febrile episodes are relatively common and represent the majority of childhood seizures. A febrile convulsion is defined as a seizure event in infancy or childhood, usually occurring between 6 months and 6 years of age, associated with fever but without any evidence of intracranial infection or defined pathologic or traumatic cause (Nabbout et al., 2002). Although the majority of patients do not develop epilepsy, the risk of developing subsequent afebrile seizures is 5 to 7 times higher in those with a history of febrile seizures compared to the general population (Annegers et al., 1987; Hedera et al., 2006).
The FEB1 locus maps to chromosome 8q13-q21.
Genetic Heterogeneity of Familial Febrile Seizures
See FEB2 (602477), caused by mutation in the HCN2 gene (602781) on chromosome 19p13; FEB3A (604403), caused by mutation in the SCN1A gene (182389) on chromosome 2q24; FEB4 (604352), caused by mutation in the ADGRV1 gene (602851) on chromosome 5q14; FEB8 (607681), caused by mutation in the GABRG2 gene (137164) on chromosome 5q31; and FEB11 (614418), caused by mutation in the CPA6 gene (609562) on chromosome 8q13.
Several loci for familial febrile seizures have been identified: see FEB3B (613863) on chromosome 2q24; FEB5 (609255) on chromosome 6q22-q24; FEB6 (609253) on chromosome 18p11; FEB7 (611515) on chromosome 21q22; FEB9 (611634) on chromosome 3p24.2-p23; and FEB10 (612637) on chromosome 3q26.
A phenotype termed 'generalized epilepsy with febrile seizures plus' (GEFS+; 604233) is a clinical subset of familial febrile convulsions in which affected individuals later develop afebrile seizures. GEFS+ is associated with mutations in several genes.
Deprez et al. (2009) provided a review of the genetics of epilepsy syndromes starting in the first year of life, and included a diagnostic algorithm.
Rich et al. (1987) performed complex segregation analysis on 467 nuclear families ascertained through probands with febrile seizures. Analyses of the entire data indicated that the single-major-locus models could be rejected. However, when families were partitioned on the basis of frequency of febrile seizures in the proband, significant heterogeneity was present. The polygenic model was strongly corroborated in families of probands with a single febrile seizure. In families with probands with multiple febrile seizures, evidence was consistent with a single-major-locus model with nearly dominant seizure susceptibility.
Johnson et al. (1996) carried out a systematic pedigree study of 52 probands; 40 of them (77%) had more than 1 case per family: 1 family had 10 cases, 1 family had 7, 3 families had 6, 2 had 5, 3 had 4, 13 had 3, and 17 had 2 cases. Mode of inheritance in the multicase families best fitted the hypothesis of autosomal dominance with reduced penetrance. Polygenic inheritance could not be excluded for some of the smaller families. There was no support for X-linked or mitochondrial inheritance. Penetrance was calculated to be 0.64. These families had been preselected for increased severity in the probands; thus, 0.64 represents a useful estimate of the upper limit of penetrance and is in agreement with twin studies.
Van Stuijvenberg et al. (1999) studied the characteristics of the first seizure in 51 children with febrile seizures with at least 1 affected first-degree relative compared to 177 affected children with no family history. No evidence for an association between familial febrile seizures and complex characteristics of the initial febrile seizure were demonstrated.
In comparing 83 cases (children with febrile seizures and a first-degree affected relative) and 101 controls (children with febrile seizures but without family history), Pal et al. (2003) found that recurrent febrile seizures were significantly associated with first-degree family history (odds ratio = 2.1). In addition, later occurrence of afebrile seizures was independently associated with recurrent febrile seizures (odds ratio = 3.47).
Febrile seizures occur in 2 to 5% of all children in the developed world before the age of 5 years (Wallace et al., 1996; Nabbout et al., 2002). In Japanese populations, the incidence is as high as 7% (Bird, 1987). In certain Pacific populations, the incidence is said to be as high as 15%. Approximately 33% of patients who experience a febrile convulsion will have a second one, and 50% of those will have a third. Two to 7% of children who experience febrile convulsions go on to develop afebrile seizure disorders and epilepsy later in life (Johnson et al., 1998).
Wallace et al. (1996) identified by linkage analysis an autosomal dominant locus for familial febrile seizures, termed FEB1, on chromosome 8q13-q21. The multipoint lod score of 3.40 was obtained, maximized over different values of penetrance and phenocopy rate, in the region flanked by markers D8S553 and D8S279. The lod score was calculated assuming the disease has a penetrance of 60% and a phenocopy rate of 3%. In the family reported by Wallace et al. (1996), Salzmann et al. (2012) excluded mutations in the CPA6 gene (609562) on chromosome 8q13. However, Salzmann et al. (2012) could not exclude the possibility of a mutation in the promoter or noncoding region, or a copy number variant in that family.
Annegers, J. F., Hauser, W. A., Shirts, S. B., Kurland, L. T. Factors prognostic of unprovoked seizures after febrile convulsions. New Eng. J. Med. 316: 493-498, 1987. [PubMed: 3807992] [Full Text: https://doi.org/10.1056/NEJM198702263160901]
Bird, T. D. Genetic considerations in childhood epilepsy. Epilepsia 28 (suppl. 1): S71-S81, 1987. [PubMed: 3113931] [Full Text: https://doi.org/10.1111/j.1528-1157.1987.tb05761.x]
Deprez, L., Jansen, A., De Jonghe, P. Genetics of epilepsy syndromes starting in the first year of life. Neurology 72: 273-281, 2009. [PubMed: 19153375] [Full Text: https://doi.org/10.1212/01.wnl.0000339494.76377.d6]
Hedera, P., Ma, S., Blair, M. A., Taylor, K. A., Hamati, A., Bradford, Y., Abou-Khalil, B., Haines, J. L. Identification of a novel locus for febrile seizures and epilepsy on chromosome 21q22. Epilepsia 47: 1622-1628, 2006. [PubMed: 17054683] [Full Text: https://doi.org/10.1111/j.1528-1167.2006.00637.x]
Johnson, E. W., Dubovsky, J., Rich, S. S., O'Donovan, C. A., Orr, H. T., Anderson, V. E., Gil-Nagel, A., Ahmann, P., Dokken, C. G., Schneider, D. T., Weber, J. L. Evidence for a novel gene for familial febrile convulsions, FEB2, linked to chromosome 19p in an extended family from the Midwest. Hum. Molec. Genet. 7: 63-67, 1998. [PubMed: 9384604] [Full Text: https://doi.org/10.1093/hmg/7.1.63]
Johnson, W. G., Kugler, S. L., Stenroos, E. S., Meulener, M. C., Rangwalla, I., Johnson, T. W., Mandelbaum, D. E. Pedigree analysis in families with febrile seizures. Am. J. Med. Genet. 61: 345-352, 1996. [PubMed: 8834046] [Full Text: https://doi.org/10.1002/(SICI)1096-8628(19960202)61:4<345::AID-AJMG8>3.0.CO;2-T]
Nabbout, R., Prud'homme, J.-F., Herman, A., Feingold, J., Brice, A., Dulac, O., LeGuern, E. A locus for simple pure febrile seizures maps to chromosome 6q22-q24. Brain 125: 2668-2680, 2002. [PubMed: 12429594] [Full Text: https://doi.org/10.1093/brain/awf281]
Pal, D. K., Kugler, S. L., Mandelbaum, D. E., Durner, M. Phenotypic features of familial febrile seizures: case-control study. Neurology 60: 410-414, 2003. [PubMed: 12578920] [Full Text: https://doi.org/10.1212/wnl.60.3.410]
Rich, S. S., Annegers, J. F., Hauser, W. A., Anderson, V. E. Complex segregation analysis of febrile convulsions. Am. J. Hum. Genet. 41: 249-257, 1987. [PubMed: 3618594]
Salzmann, A., Guipponi, M., Lyons, P. J., Fricker, L. D., Sapio, M., Lambercy, C., Buresi, C., Bencheikh, B. O. A., Lahjouji, F., Ouazzani, R., Crespel, A., Chaigne, D., Malafosse, A. Carboxypeptidase A6 gene (CPA6) mutations in a recessive familial form of febrile seizures and temporal lobe epilepsy and in sporadic temporal lobe epilepsy. Hum. Mutat. 33: 124-135, 2012. [PubMed: 21922598] [Full Text: https://doi.org/10.1002/humu.21613]
van Stuijvenberg, M., van Beijeren, E., Wils, N. H., Derksen-Lubsen, G., van Duijn, C. M., Moll, H. A. Characteristics of the initial seizure in familial febrile seizures. Arch. Dis. Child. 80: 178-180, 1999. [PubMed: 10325737] [Full Text: https://doi.org/10.1136/adc.80.2.178]
Wallace, R. H., Berkovic, S. F., Howell, R. A., Sutherland, G. R., Mulley, J. C. Suggestion of a major gene for familial febrile convulsions mapping to 8q13-21. J. Med. Genet. 33: 308-312, 1996. [PubMed: 8730286] [Full Text: https://doi.org/10.1136/jmg.33.4.308]