HCN2

Inheritance Pattern: AD

Disease ID:MONDO:0005027

Submitter: ClinGen

*HCN2* was first reported to have a potential link to autosomal dominant epilepsy in 2008 (Tang B et al., PMID: 17931874). Some case-level data exists to suggest a possible gene-disease relationship. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found differences in molecular mechanism, inheritance pattern, and phenotype for *HCN2*-related disorders. Therefore, the following disease entities have been split into multiple curations: autosomal recessive complex neurodevelopmental disorder, autosomal dominant complex neurodevelopmental disorder, and autosomal dominant epilepsy (this curation). The split curations for autosomal recessive and autosomal dominant complex neurodevelopmental disorder are presented separately. Four missense variants reported in five probands from three publications are included in this curation (PMID: 24324597, 29064616, 40468825). The phenotype consisted of febrile, generalized, and/or focal seizures, sometimes noted to be photosensitive. Seizures were isolated or associated with borderline/mild intellectual disability. Though these probands have overlapping features with those described in the AD complex neurodevelopmental disorder curation, co-expression of these variants with wild type *HCN2* in Xenopus oocytes indicates these variants exhibit a depolarizing shift in activation, a greater slope, and faster activation kinetics compared to controls, consistent with a gain-of-function effect (PMID: 24324597, 29064616, 40468825) (as opposed to a dominant-negative effect observed in the AD complex neurodevelopmental disorder curation). Additionally, most variants in the autosomal dominant complex neurodevelopmental disorder curation were do novo, while most variants in this curation were inherited from affected parents. Other missense variants were given zero points due to a lack of detailed clinical information, lack of segregation in affected family members, higher than expected population frequency in gnomAD v4.1.0, and/or functional studies showing no significant difference in channel properties compared to wild-type (PMIDs: 17931874, 21615589, 29064616, 20437590, 28807990). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Epilepsy GCEP on the meeting date February 3, 2026 (SOP Version 11).

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*HCN2* was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2023 (DiFrancesco JC et al., PMID: 37746765). Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found differences in molecular mechanism, inheritance pattern, and phenotype for *HCN2*-related disorders. Therefore, the following disease entities have been split into multiple curations: autosomal recessive complex neurodevelopmental disorder, autosomal dominant complex neurodevelopmental disorder (this curation), and autosomal dominant epilepsy. The split curations for autosomal recessive complex neurodevelopmental disorder and autosomal dominant epilepsy are presented separately. Six variants, including missense and in-frame substitutions, reported in eleven probands from three publications are included in this curation (PMID: 37746765, 37853563, 40468825). Clinical features associated with heterozygous variants in the *HCN2* gene causing complex neurodevelopmental disorder include mild to severe intellectual disability, sometimes associated with epilepsy, movement disorders, hypotonia, or nystagmus. Several recurrent variants have been reported in unrelated probands, including c.1432_1434del (p.(E478del)), c.1088 C>T (p.(A363V)), and c.1379G>A (p.(G460D)). The mechanism of pathogenicity is reported to be dominant negative (PMID: 40468825) and the variants are typically de novo. Co-expression of several of these variants with wild type *HCN2* in Xenopus oocytes indicates they exhibit lower conductance, faster kinetics, and open at more hyperpolarizing potential than wild type *HCN2*, consistent with partial loss-of-function and a dominant negative effect of the variant on channel function (PMID: 40468825). In summary, there is definitive evidence supporting the relationship between *HCN2* and autosomal dominant neurodevelopmental disorder. This has been repeatedly demonstrated in the clinical diagnostic setting and has been upheld over time. This classification was approved by the ClinGen Epilepsy GCEP on the meeting date February 3, 2026 (SOP Version 11).

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: ClinGen

*HCN2* was first reported in relation to autosomal recessive complex neurodevelopmental disorder in 2011 (DiFrancesco JC et al., PMID: 22131395). Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found differences in molecular mechanism, inheritance pattern, and phenotype for *HCN2*-related disorders. Therefore, the following disease entities have been split into multiple curations: autosomal recessive complex neurodevelopmental disorder (this curation), autosomal dominant complex neurodevelopmental disorder, and autosomal dominant epilepsy. The split curations for the two autosomal dominant *HCN2*-related disorders are presented separately. Six variants, including missense and frameshift substitutions, reported in six homozygous probands from three publications are included in this curation (PMID: 22131395, 30237576, 40468825). Clinical features associated with biallelic variants in the *HCN2* gene include mild to severe intellectual disability, sometimes associated with epilepsy, movement disorders, hypotonia, or nystagmus. The mechanism of pathogenicity is known to be loss of function; functional studies in select missense variants demonstrated complete loss of function (PMID: 40468825). This gene-disease relationship is supported by mouse models. *HCN2*-deficient mice are smaller, ataxic, and have spontaneous seizures (PMIDs: 12514127, 19150498). In summary, there is definitive evidence supporting the relationship between *HCN2* and autosomal recessive neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Epilepsy GCEP on the meeting date February 3, 2026 (SOP Version 11).