Submission Details

KCNA2 was first reported in relation to autosomal dominant developmental and epileptic encephalopathy (DEE) in 2015 (Pena et al., 2015, PMID: 25477152). The gene encodes the voltage-gated "Shaker" potassium channel, which is a member of the Kv1 subfamily and assembles into homo- or hetero-tetrameric channels (PMID: 29050392). The mechanism for disease is heterozygous missense variants that may have either gain-of-function, loss-of-function, or mixed effect on the potassium channel activity as measured by patch clamp recording in Xenopus laevis oocytes, or heterozygous truncating variants resulting in loss of channel function (PMID: 29050392, 25751627). The clinical presentation is variable but typically includes infantile-onset generalized and/or focal seizures associated with developmental delay, intellectual disability, and evidence of cerebellar dysfunction such as ataxia and dysarthria (Doering et al., 2021, PMID: 33802230; Masnada et al., PMID: 29050392). Of note, this gene has also been implicated in autosomal dominant complicated hereditary spastic paraplegia, which is not assessed in this curation since these individuals did not have epilepsy (Helbig et al., 2016, PMID: 27543892 ; Manole et al., 2017 PMID: 28032718; ).

Included in this curation are 10 missense or nonsense variants have been reported in 17 probands from 8 publications (PMIDs: 31054490, 29050392, 27733563, 27117551, 27062609, 26648591, 25477152, 25751627). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Nearly all probands included in the curation have confirmed or assumed de novo variants. There are three recurrent de novo variants (c.890G>A (p.Arg297Gln), c.1214C>T (p.Pro405Leu), c.1120A>G (p.Thr374Ala)) that account for ~2/3 of all reported patients (PMID: 29050392). This gene-disease association is also supported by experimental evidence including biochemical function indicating a role for Kv1.2 channels in the regulation of state transitions and repetitive discharge in medium spiny neurons (PMID: 13679409) and in expression data indicating the variant is widely expressed in the CNS, including in glutamergic pyramidal cells, GABAergic interneurons, and juxtaparanodal axons, and there is co-expression with Kv1.1, which is encoded by KCNA1 (PMID: 19118165).

In summary, KCNA2 is definitively associated with autosomal dominant DEE. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.