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| Childhood onset dystonia, chorea or related movement disorder v7.17 | HCN2 | Ida Ertmanska Classified gene: HCN2 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Childhood onset dystonia, chorea or related movement disorder v7.17 | HCN2 | Ida Ertmanska Added comment: Comment on list classification: In a cohort of 21 patients with HCN2 variants (mono- and bi- allelic), 12 presented with movement disorders, including dystonia, tremor, cerebellar signs, and stereotypies. Hence, this gene should be promoted to Green on Childhood onset dystonia, chorea or related movement disorder with MOI BOTH monoallelic and biallelic, autosomal or pseudoautosomal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Childhood onset dystonia, chorea or related movement disorder v7.17 | HCN2 | Ida Ertmanska Gene: hcn2 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Childhood onset dystonia, chorea or related movement disorder v7.16 | HCN2 |
Ida Ertmanska gene: HCN2 was added gene: HCN2 was added to Childhood onset dystonia, chorea or related movement disorder. 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 Added comment: 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 |
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