Submission Details

Variants in KCNH5 were first reported in an individual with mild motor delay, severe language delay, and epileptic encephalopathy in 2013 (Veeramah et al., PMID: 23647072). Since that time, numerous other individuals with variants in this gene have been reported with features such as intellectual disability, language and developmental delays, and a variety of seizure types. While severity of intellectual disability and developmental delays have been reported to vary across probands, seizures onset in the first year of life across all cases that were reviewed. For this reason, the Epilepsy GCEP has decided to curate this information under the disease term infantile-onset epilepsy (MONDO:0100207).

Seven missense variants were reported in 19 probands across four publications (PMIDs: 23647072, 32725632, 35874597, 36307226) and one splice site in one proband (PMID:35874597). Two recurrent missense variants, p.Arg327His and p.Arg333His, were recorded in 10 and 4 patients respectively. Most of the observed variants were characterized as de novo in the probands, although there is one case of inheritance from an affected mother. Of note, genotype-phenotype correlations were described in one paper (PMID:36307226). Functional studies for one recurrent missense variant, p.Arg327His, demonstrate a gain of function effect, though these types of studies have not been performed to confirm the mechanism of other variants. The gene-disease relationship is further supported by animal model and rescue studies (PMID:31728858). Additional experimental evidence is also available in the literature (PMID 32222671).

In summary, there is definitive evidence to support the relationship between KCNH5 and autosomal dominant infantile-onset epilepsy (MONDO:0100207). This has been repeatedly demonstrated and has been upheld over time. This was approved by the ClinGen Epilepsy GCEP on November 15th, 2022 (SOP Version 9).