Other entities represented in this entry:
DO: 0111310;
Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38): 19:1-6,900,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.3 | Febrile seizures, familial, 2 | 602477 | Autosomal dominant | 2 |
A number sign (#) is used with this entry because of evidence that susceptibility to various types of seizure disorders, including idiopathic generalized epilepsy-17 (EIG17), generalized epilepsy with febrile seizure plus, type 11 (GEFSP11), and familial febrile seizures-2 (FEB2), is conferred by heterozygous mutation in the HCN2 gene (602781) on chromosome 19p13. One patient with a homozygous HCN2 variant has been reported.
Mutation in the HCN2 gene can cause a spectrum of seizure disorders beginning in childhood or adolescence. Affected individuals may have simple febrile seizures or more complex afebrile seizures, including tonic-clonic, myoclonic, and photosensitive. Rare patients may have mild intellectual disability or behavioral problems (summary by Li et al., 2018).
For a general phenotypic description and a discussion of genetic heterogeneity of idiopathic generalized epilepsy, see EIG (600669).
For a phenotypic description and a discussion of genetic heterogeneity of familial febrile seizures, see FEB1 (121210).
For a general phenotypic description and a discussion of genetic heterogeneity of GEFS+, see 604233.
DiFrancesco et al. (2011) reported a 28-year-old man who had onset of generalized epilepsy with absence and tonic-clonic seizures at age 12. There was no history of febrile seizures. EEG showed generalized sharp-wave complexes; brain imaging was normal. He had initial response to lamotrigine, but developed side effects. There was no family history of a seizure disorder.
Nakamura et al. (2013) reported 2 unrelated Japanese children with febrile seizures. One of the children had a similarly affected mother who had febrile seizures in childhood, consistent with autosomal dominant inheritance. Clinical details were limited.
Li et al. (2018) reported 7 patients from 3 unrelated families with various types of seizure disorders associated with mutations in the HCN2 gene. In 1 family, a woman and her daughter both had idiopathic photosensitive occipital lobe epilepsy, whereas the woman's son had febrile seizures. In a second family, 2 Italian brothers had early-onset absence seizures. One brother had onset of absence seizures at age 3 years, followed by generalized tonic-clonic seizures and spike-wave discharges on EEG in adolescence, whereas the other had absence seizures associated with photosensitivity. Three affected individuals in a third family were diagnosed with idiopathic photosensitive occipital lobe epilepsy, photosensitive generalized epilepsy, and an unclassified epilepsy, respectively. These patients had onset of myoclonic or focal seizures between 6 years and adolescence. EEG showed spike-wave discharges and centrotemporal spikes. One patient also had mild intellectual disability, and her affected sib had behavioral problems, mainly ADHD.
The transmission pattern of FEB2 in the family reported by Nakamura et al. (2013) was consistent with autosomal dominant inheritance.
The transmission pattern of EIG17 in the families reported by Li et al. (2018) was consistent with autosomal dominant inheritance with variable expressivity.
The transmission pattern of EIG17 in the family reported by DiFrancesco et al. (2011) was consistent with autosomal recessive inheritance.
Johnson et al. (1998) identified an autosomal dominant febrile convulsion locus on 19p. Linkage analysis in a large family from the American Midwest gave a maximum pairwise lod score of 4.52 with marker Mfd120 at locus D19S177. Haplotype analysis using both affected and unaffected family members indicated that the chromosome 19 febrile seizure gene, FEB2, can be localized to an 11.7-cM, 1- to 2-Mb section of 19p13.3, between loci D19S591 and D19S395.
Dibbens et al. (2010) identified a variant in the HCN2 gene that resulted in a 9-bp deletion (2156delCGCCGCCGC) removing 3 proline residues at 719 to 721 (delPPP) from a 7-proline repeat close to the cyclic nucleotide-binding domain (602781.0001). The deletion was present in 3 (2.3%) of 65 patients with generalized epilepsy with febrile seizures plus (GEFSP11) and in 3 (2.5%) of 61 patients with febrile seizures (FEB2), whereas it was present in only 3 (0.2%) of 772 controls. In vitro functional expression studies in Xenopus oocytes showed that the delPPP variant had a 35% increase in current size in response to hyperpolarization compared to wildtype. This current increase would depolarize the membrane potential, taking the neuron closer to the firing potential, and thus could enhance neuronal excitability. The HCN2 delPPP variant was not observed in patients with idiopathic generalized epilepsy who did not have febrile seizures.
In 2 unrelated Japanese children with febrile seizures, Nakamura et al. (2013) identified a heterozygous missense variant in the HCN2 gene (S126L; 602781.0002). The mutations were found by direct sequencing of the HCN2 gene among a cohort of 160 children with febrile seizures. In 1 case, the S126L variant was inherited from a similarly affected mother. Electrophysiologic studies in HEK293 cells expressing the mutation showed that it had elevated sensitivity to increased temperature compared to controls. The mutant channels showed faster activation, a greater depolarizing shift, and increased current density at higher temperatures compared to wildtype. The findings suggested that S126L mutant channels may augment neuronal excitability during hyperthermia.
In affected individuals from 3 unrelated families with EIG17, Li et al. (2018) identified heterozygous missense mutations in the HCN2 gene (S632W, 602781.0003 and V246M, 602781.0004). The mutations, which were found by direct sequencing of 585 patients with suspected genetic epilepsy, segregated with the disorder in the families from whom DNA was available. In vitro electrophysiologic studies showed that both mutations caused a depolarizing shift in activation, a greater slope, and faster activation kinetics compared to controls, consistent with a gain-of-function effect. These findings were also observed when expressed with wildtype, indicating a dominant effect.
Homozygous Mutation
In a 28-year-old man with autosomal recessive EIG17, DiFrancesco et al. (2011) identified a homozygous missense variant in the HCN2 gene (E515K; 602781.0005). The mutation, which was found by direct sequencing, was present in the heterozygous state in multiple family members who did not have seizures. In vitro functional expression studies in CHO cells showed that the homomeric mutant, but not heteromeric mutant/wildtype channels, were inhibited. There was a large negative shift of activation with lowering of the activation threshold and slowed activation kinetics, effectively abolishing HCN2 contribution to resting activity, consistent with a loss-of-function effect. Transfection of the mutation into rat cortical neurons resulted in similar changes, as well as an increase in cell excitability and firing frequency compared to wildtype.
Chung et al. (2009) identified a spontaneous recessive mouse mutant, 'apathetic' (ap/ap), that shows ataxia, uncoordinated motor movements, and seizures resembling generalized absence and tonic-clonic convulsions. Some heterozygous mice showed absence seizures, and most had enhanced susceptibility to chemoconvulsive seizures, consistent with neuronal hyperexcitability. The associated mutation was a frameshift in the murine Hcn2 gene, resulting in a loss of protein expression and function. The findings suggested that I(h) channels are critical for maintaining normal neuronal network oscillations.
Chung, W. K., Shin, M., Jaramillo, T. C., Leibel, R. L., LeDuc, C. A., Fischer, S. G., Tzilianos, E., Gheith, A. A., Lewis, A. S., Chetkovich, D. M. Absence epilepsy in apathetic, a spontaneous mutant mouse lacking the h channel subunit, HCN2. Neurobiol. Dis. 33: 499-508, 2009. [PubMed: 19150498] [Full Text: https://doi.org/10.1016/j.nbd.2008.12.004]
Dibbens, L. M., Reid, C. A., Hodgson, B., Thomas, E. A., Phillips, A. M., Gazina, E., Cromer, B. A., Clarke, A. L., Baram, T. Z., Scheffer, I. E., Berkovic, S. F., Petrou, S. Augmented currents of an HCN2 variant in patients with febrile seizure syndromes. Ann. Neurol. 67: 542-546, 2010. [PubMed: 20437590] [Full Text: https://doi.org/10.1002/ana.21909]
DiFrancesco, J. C., Barbuti, A., Milanesi, R., Coco, S., Bucchi, A., Bottelli, G., Ferrarese, C., Franceschetti, S., Terragni, B., Baruscotti, M., DiFrancesco, D. Recessive loss-of-function mutation in the pacemaker HCN2 channel causing increased neuronal excitability in a patient with idiopathic generalized epilepsy. J. Neurosci. 31: 17327-17337, 2011. [PubMed: 22131395] [Full Text: https://doi.org/10.1523/JNEUROSCI.3727-11.2011]
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]
Li, M., Maljevic, S., Phillips, A. M., Petrovski, S., Hildebrand, M. S., Burgess, R., Mount, T., Zara, F., Striano, P., Schubert, J., Thiele, H., Nurnberg, P., Wong, M., Weisenberg, J. L., Thio, L. L., Lerche, H., Scheffer, I. E., Berkovic, S. F., Petrou, S., Reid, C. A. Gain-of-function HCN2 variants in genetic epilepsy. Hum. Mutat. 39: 202-209, 2018. [PubMed: 29064616] [Full Text: https://doi.org/10.1002/humu.23357]
Nakamura, Y., Shi, X., Numata, T., Mori, Y., Inoue, R., Lossin, C., Baram, T. Z., Hirose, S. Novel HCN2 mutation contributes to febrile seizures by shifting the channel's kinetics in a temperature-dependent manner. PLoS One 8: e80376, 2013. [PubMed: 24324597] [Full Text: https://doi.org/10.1371/journal.pone.0080376]