HCN1 – Generalized Epilepsy with Febrile Seizures Plus Spectrum

HCN1 encodes the hyperpolarization-activated cyclic nucleotide-gated channel 1, a key regulator of neuronal Ih current. Initial exome sequencing in 2014 identified five individuals with de novo HCN1 variants presenting with early infantile epileptic encephalopathy (PMID:24747641). This report provided the first clinical link between HCN1 dysfunction and severe epilepsy.

To define the broader phenotype, a 2018 cohort assembled 33 unpublished patients harboring novel pathogenic or likely pathogenic HCN1 variants: 19 probands carrying 14 different de novo mutations and four families with dominantly inherited variants segregating with epilepsy in 14 affected relatives but not in six additional individuals (PMID:30351409). Sporadic cases had median seizure onset at 7 months, with 36% experiencing seizures during febrile illness. Predominant presentations spanned mild genetic generalized epilepsies to the GEFS+ spectrum, while ~20% manifested neonatal/infantile epileptic encephalopathy.

The variant spectrum is exclusively missense, with severe phenotypes clustering within or near transmembrane domains and milder phenotypes linked to intracellular N- and C-terminal regions. A representative pathogenic allele is c.1172G>T (p.Gly391Val). Five recurrent variants demonstrated consistent genotype–phenotype correlations across unrelated families.

Functional validation via whole-cell patch-clamp in heterologous cells showed biophysical impacts ranging from complete loss-of-function to significant shifts in activation kinetics and voltage dependence (PMID:30351409). Notably, the Gly391Asp variant produced the greatest channel dysfunction, mirroring the most severe neonatal phenotype. Molecular dynamics simulations revealed cation-mediated pore block in homotetramers and altered gating in heterotetramers.

Knock-in mouse models of human HCN1 variants (p.Gly391Asp and p.Met153Ile) recapitulate spontaneous seizures and exhibit paradoxical seizure induction upon sodium channel blocker administration, consistent with patient drug responses (PMID:35972069). These models confirm a dominant-negative mechanism and underscore the need for variant-specific therapeutic strategies.

Incomplete penetrance in familial cases and isolated reports of adult genetic generalized epilepsy, such as a de novo c.469C>G (p.Leu157Val) variant causing typical GGE (PMID:29936235), highlight variable expressivity within the GEFS+ spectrum.

Together, robust de novo and segregation data across 33 families, concordant functional assays, and validated animal models support a Strong clinical validity classification for HCN1 in GEFS+ spectrum. HCN1 screening is recommended in patients with febrile seizures and generalized epilepsy. Key take-home: HCN1 pathogenic variants underlie a dominantly inherited GEFS+ spectrum with variable severity and demand precision therapy based on functional impact.

References

• Brain : a journal of neurology • 2018 • HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond. PMID:30351409
• Nature Genetics • 2014 • De novo mutations in HCN1 cause early infantile epileptic encephalopathy. PMID:24747641
• eLife • 2022 • Seizures, behavioral deficits, and adverse drug responses in two new genetic mouse models of HCN1 epileptic encephalopathy. PMID:35972069
• Neurobiology of Disease • 2018 • A novel de novo HCN1 loss-of-function mutation in genetic generalized epilepsy causing increased neuronal excitability. PMID:29936235

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