Case‐control pharmacogenetic study of HCN1/HCN2 variants and genetic generalized epilepsies

Abstract

Epilepsy is a common complex neurological disorder, and some forms are resistant to drug treatment. The HCN1/HCN2 genes encode hyperpolarization-activated cyclic nucleotide-gated channels, which play important roles in the electrophysiology of neurons. We investigated the association between HCN1/HCN2 variants and drug resistance or the risk of genetic generalized epilepsies (GGEs). We used matrix-assisted laser desorption/ionization time-of-flight mass spectrometry to assess nine variants of HCN1/HCN2 in 284 healthy participants and 483 GGEs (279 drug-responsive, 204 drug-resistant). Frequencies of HCN2 rs7255568 and rs3752158 G alleles differed in GGEs and in controls (P = .039, P = .027, respectively). The frequency of HCN2 haplotype (CAC) was higher in patients than controls (P = .046). The frequency of the HCN1 rs10462087 CC+CT genotype was lower in patients with childhood absence epilepsy (CAE) than controls (P = .047). Rs7255568 was associated with the risk of CAE (P = .028) and juvenile myoclonic epilepsy (JME) (P = .02). Rs3752158 was associated with the risk of generalized tonic-clonic seizures, JME, and febrile seizures (all P < .05). The frequency of the HCN2 haplotype (CAC) was higher in patients with JME (P = .015) and in those with febrile seizures (P = .024) than in controls. No significant association was found between HCN1/HCN2 alleles, genotypes or haplotypes, and drug resistance in patients. After Bonferroni's multiple comparisons correction, only the HCN2 rs3752158 C allele and GC+CC genotype frequencies in patients with JME were higher than those in controls (19.2% vs 11.6%, odds ratio (OR) = 1.71, 95% CI = 1.18-2.32), P = .004 < 0.05/9; 36% vs 22.2%, OR = 1.62(1.18-2.23), P = .003 < 0.05/9). Our study suggests that HCN2 rs3752158 is involved in the susceptibility to JME.

Next‐generation sequencing improves treatment efficacy and reduces hospitalization in children with drug‐resistant epilepsy

“…During the last few years, accumulated evidence supports the strong role of genetics in unexplained DRE patients . Moreover, advances in clinical testing technology have increased the diagnostic yield from 10% a few years ago to 30%‐40%.…”

“…During the last few years, accumulated evidence supports the strong role of genetics in unexplained DRE patients. [7][8][9][10] Moreover, advances in clinical testing technology have increased the diagnostic yield from 10% a few years ago to 30%-40%. This increase has primarily been technology-driven, due to the development of nextgeneration sequencing (NGS).…”

Genetics in epilepsy, Dravet and SUDEP: A systematic review

“…It is the gene responsible for coding the H channel, subunit number 2, for activated cations by cyclic nucleotide and for hyperpolarization, [21][22][23] has high sensitivity to cAMP modulation, and is located especially in the thalamus and trunk region. Studies have identified modifications in HCN2 Gs rs7255568 and rs3752158 alleles in genetically generalized epilepsies (GGEs) determined, regarding to controls (p=0.039, p=0.027, respectively).…”

“…Studies have identified modifications in HCN2 Gs rs7255568 and rs3752158 alleles in genetically generalized epilepsies (GGEs) determined, regarding to controls (p=0.039, p=0.027, respectively). 21 Only rs7255568 was linked to risks of childhood absence epilepsy (CAE) (p=0.028) and juvenile myoclonic epilepsy (JME) (p=0.02). 21 While rs3752158 is linked to the risk of generalized tonic-clonic seizures, JME and febrile seizures, in all C and GC + CC alleles.…”

“…21 Only rs7255568 was linked to risks of childhood absence epilepsy (CAE) (p=0.028) and juvenile myoclonic epilepsy (JME) (p=0.02). 21 While rs3752158 is linked to the risk of generalized tonic-clonic seizures, JME and febrile seizures, in all C and GC + CC alleles. 21,33 Changes in the two previously mentioned alleles, as well as variations of R527Q in HCN2 exon 5 are also present in congenital rigid spine muscular dystrophy.…”