Early onset or syndromic epilepsy

Gene: HCN2

Green List (high evidence)

PMID: 40468825 Houdayer et al., 2025
21 individuals with HCN2 variants from 15 unrelated families - 13 monoallelic cases and 8 biallelic. The phenotypic spectrum included developmental delay/intellectual disability (DD/ID, 17/21), epilepsy (10/21), language disorders (16/21), movement disorders (12/21), and axial hypotonia (10/21).
Movement disorders included dystonia, tremor, cerebellar signs, stereotypies. Muscle tone abnormalities included axial hypotonia, hypertonia, pyramidal signs and spasticity. Biallelic LOF cases uniformly presented with severe intellectual disability, while monoallelic cases showed mild to moderate ID (IQ 40-60) with evidence of skill regression. Heterozygous GOF variants resulted in borderline ID and milder epilepsy phenotype.
Thirteen pathogenic HCN2 variants (12 new and 1 already described) were identified: 11 missense, 1 recurrent inframe deletion, and 1 frameshift.

Functional evidence: electrophysiology with Xenopus laevis oocytes and membrane trafficking investigated in HEK cells - p.(Arg324His) variant showed a strong increase of HCN2 conductance; p.(Ala363Val) and p.(Met374Leu) exhibited dominant negative effects. The p.(Leu377His), p.(Pro493Leu), and p.(Gly587Asp) variants rendered HCN2 electrophysiologically silent and impaired membrane trafficking. Structural 3D-analysis revealed that, except for p.(Arg324His), all variants altered HCN2 stability.

HCN2 is associated with several AD phenotypes in OMIM: Generalized epilepsy with febrile seizures plus, type 11 602477; Febrile seizures, familial, 2 602477; {Epilepsy, idiopathic generalized, susceptibility to, 17} 602477 - all same MIM number (accessed 12th Mar 2026). Not yet added to ClinGen or Gene2Phenotype.

Created: 12 Mar 2026, 2:26 p.m. | Last Modified: 12 Mar 2026, 2:26 p.m.

Panel Version: 8.143

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Generalized epilepsy with febrile seizures plus, type 11, OMIM:602477; neurodevelopmental disorder, MONDO:0700092

Publications

• 40468825

I don't know

No phenotype association on OMIM. HGMD Pro: no of reported variants associated with epilepsy phenotypes: Li et al 2018 (29064616): 4 different variants identified in HCN2 (3 missense 1 fs - all AD inheritance)- all affecteds had a seizure phenotype: 2 unrelated individuals with seizures had the same missense variant. In one family it was shown to segregate with disease in aff brother and mother. The fs variant did not appear to segregate with disease. Functional studies on two of the missense variants (Ser632Trp & Val246Met) suggest GOF. Dibbens et al, 2010 (20437590): in frame deletion of 3 AA in HCN2 which was found to be het in 3/65 GEFS+ unrelated patients, 3/61 FS unrelated patients, and 3/772 blood bank controls.Dewar et al, 2017 (28807990) - reclassified this variant as benign. DiFrancesco, 2019 & 2011 (30986657 & 221311395) 2011 paper identified first recessive missense variant - causing a nearly complete LOF of the channel, het carriers didn't appear to have any features. In the 2019 paper, identify 6 het missense variants - however they only think that the Glu515Lys variant (that they prev reported in a hom case) as being of interest. Nakamura et al, 2013 (24324597) - 2 unrelated children with FS where carriers of a het missense HCN2 variant. In one family the mother also had the variant and suffered from FS. I think class as amber.

Created: 5 Sep 2019, 2:22 p.m. | Last Modified: 5 Sep 2019, 2:22 p.m.

Panel Version: 1.261

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Green List (high evidence)

No phenotype association link in OMIM; 5 DM variants in HGMDPro with an association with an epilepsy phenotype. PMID 29064616 details several individuals with mainly missense variants in this gene and epilepsy/seizures (pedigrees suggest a dominant MOI). Functional studies in this paper also showed a depolarising shift in activation fot the p.(Ser632Trp) and p.(Val246Met) variants consistent with a gain-of-function. Additionally, PMID 22131395 identified the p.(Glu515Lys) variant in a large family and suggested that homozygosity is associated with epilepsy in this instance as this variant exhibits LOF.

Created: 23 Aug 2019, 9:54 a.m. | Last Modified: 23 Aug 2019, 9:54 a.m.

Panel Version: 1.256

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Publications

• 29064616
• 22131395

I don't know

more information required

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

• 29064616

I don't know

As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Although this is a borderline case with questions over phenotype segregation, there are sufficient cases to support inclusion. Although seizures aren’t one of the cardinal phenotypes, most cases will be trios and therefore there will be less issues in being inclusive. Kept rating of HCN2 as Green with the option of review on subsequent panel versions.

Created: 25 Nov 2019, 8:17 p.m. | Last Modified: 25 Nov 2019, 8:17 p.m.

Panel Version: 1.426

Comment on mode of inheritance: Kept MOI as 'BOTH monoallelic and biallelic' as supported by reviews from Helen Lord and Alison Callaway, and literature (PMID:22131395).

Created: 19 Nov 2019, 10:37 p.m. | Last Modified: 19 Nov 2019, 10:37 p.m.

Panel Version: 1.408

Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset that were re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.

Created: 5 Sep 2019, 2:26 p.m. | Last Modified: 5 Sep 2019, 2:26 p.m.

Panel Version: 1.262

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor. Suggested gene rating: Amber.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Comment on mode of inheritance: PMID:22131395: DiFrancesco et al. 2011 report a homozygous HCN2 variant (p.E515K) in a patient with idiopathic generalized epilepsy. Of 17 screened members of the same family, the proband was the only one affected and homozygous for the variant. This is the first evidence in humans for a single-point, homozygous loss-of-function mutation in HCN2 potentially associated with generalized epilepsy with recessive inheritance. Hence MOI listed as BOTH monoallelic and biallelic.

Created: 11 Jul 2019, 4:27 p.m. | Last Modified: 13 Aug 2019, 10:49 a.m.

Panel Version: 1.198

Comment on list classification: Promoted from amber to green. No phenotypes have been associated with HCN2 in OMIM or Gene2Phenotype. There are 2 papers (PMID: 29064616, 17931874) reporting misssense, frameshift and small deletion variants in HCN2 associated with Genetic epilepsy with febrile seizures plus disorders and other epilepsy/seizure disorders (e.g. Idiopathic generalized epilepsy). There is also evidence that these variants cause gain-of-function effects (PMID: 29064616). Another study reported on a patient with sporadic idiopathic generalised seizures who had a recessive loss-of-function missense variant. An HCN2 knockout mouse model (PMID: 12514127) had absence seizures.

Created: 23 Nov 2018, 4:35 p.m.

Green List (high evidence)

Multiple patients reported with different seizure disorders and variants in this gene. There is evidence that the variants are gain-of-function.

Created: 15 Aug 2018, 12:56 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
GEFS+ and other seizure disorders

Publications

• 29064616, 24324597, 20437590

Mode of pathogenicity
Other

Variants in this GENE are reported as part of current diagnostic practice