Intellectual disability
Gene: HCN2

HCN2 (hyperpolarization activated cyclic nucleotide gated potassium and sodium channel 2)
EnsemblGeneIds (GRCh38): ENSG00000099822
EnsemblGeneIds (GRCh37): ENSG00000099822
OMIM: 602781, Gene2Phenotype
HCN2 is in 3 panels

1 review

Ida Ertmanska (Genomics England Curator)

Green List (high evidence)

Comment on list classification: In a cohort of 21 patients with HCN2 variants (mono- and bi- allelic), 17 presented with syndromic ID/DD, often severe. Hence, this gene should be promoted to Green on Intellectual disability with MOI BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Created: 12 Mar 2026, 2:38 p.m. | Last Modified: 12 Mar 2026, 2:38 p.m.

Panel Version: 9.301

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.
Sources: Literature
Created: 12 Mar 2026, 2:33 p.m.

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

Created: 12 Mar 2026, 2:33 p.m.

Panel version: 9.300

Details

Mode of Inheritance

BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Sources

Expert Review Amber
Literature

Phenotypes

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

Tags

Q1_26_promote_green

OMIM

602781

Clinvar variants

Variants in HCN2

Penetrance

None

Publications

40468825

Panels with this gene

History Filter Activity

12 Mar 2026, Gel status: 2

Entity classified by Genomics England curator

Ida Ertmanska (Genomics England Curator)

Gene: hcn2 has been classified as Amber List (Moderate Evidence).

12 Mar 2026, Gel status: 1

Created, Added New Source, Added Tag, Set mode of inheritance, Set publications, Set Phenotypes

Ida Ertmanska (Genomics England Curator)

gene: HCN2 was added gene: HCN2 was added to Intellectual disability. Sources: Literature Q1_26_promote_green tags were added to gene: HCN2. Mode of inheritance for gene: HCN2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: HCN2 were set to 40468825 Phenotypes for gene: HCN2 were set to Generalized epilepsy with febrile seizures plus, type 11, OMIM:602477; neurodevelopmental disorder, MONDO:0700092 Review for gene: HCN2 was set to GREEN

Intellectual disability Gene: HCN2