Early onset or syndromic epilepsy

Gene: KCND3

Green List (high evidence)

The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.

Created: 11 Mar 2026, 3:39 p.m. | Last Modified: 11 Mar 2026, 3:39 p.m.

Panel Version: 8.134

Comment on list classification: Promoting to amber with a recommendation for green rating following GMS review.

Created: 5 Oct 2025, 10:51 p.m. | Last Modified: 5 Oct 2025, 10:51 p.m.

Panel Version: 8.38

Green List (high evidence)

Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant neurodevelopmental phenotypes - including epilepsy. There are published articles with at least 5 unrelated individuals with early-onset syndromic epilepsy (PMIDs:26189493; 28947073; 32823520; 32921676). While the penetrance is incomplete, childhood onset epilepsy may be the first presenting symptom in a patient.
Knock-in mice (p.Phe227del equivalent) displayed defects in motor coordination and balance, and neuroinflammation. Knock-out Kcnd3 -/- mice showed no observable phenotype. Molecular evidence suggests that the misfolded protein induces a trafficking defect in the Golgi apparatus - a dominant negative effect (PMID: 39562497).
Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.

Created: 3 Oct 2025, 4:08 p.m. | Last Modified: 3 Oct 2025, 4:23 p.m.

Panel Version: 8.37

KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19 (SCA 19) - progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). A range of additional phenotypes has also been reported, with variable penetrance: developmental delay and cognitive impairment; myoclonus, dystonia, rigidity, seizures. There are several reports of individuals with KCND3 variants and syndromic childhood-onset epilepsy:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability (onset at 3yo), epilepsy, ADHD, strabismus, oral apraxia and joint hyperlaxity. Frequent nocturnal muscle jerks, episodes of staring and severe concentration problems occurred at 5yo. Epilepsy successfully treated with valproate, stopped at age 9.
Heterozygous for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) - not in gnomAD v4. Sequencing method: WES. Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 28947073 Huin et al., 2017
Two unrelated French families with SCA19/22; affected individuals het for KCND3 c.679_681del p.(Phe227del) - variant not in gnomAD v4. Method: targeted seq of 24 ataxia genes. KCND3 mutation segregated with disease.
11/16 patients developed classic SCA19/22 i.e. slowly progressing cerebellar ataxia, gait impariment, average onset at 23.1 yrs. No seizures reported.
5/16 affected patients presented with epilepsy (mean age of onset 5.3 years) - ataxia was mild or not reported in those patients.

PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID, speech difficulties; suffered from focal and generalised motor seizures around age 5 - abnormal EEG recorded, epilepsy successfully treated with carbamazepine.
Brain MRI was normal at age 5; at age 23 MRI revealed isolated vermis atrophy.
Variant: de novo c.901T>C p.(Ser301Pro) in KCND3. Discrepant frequencies in gnomAD between exome and genome (not reliable). Seq method: WES.

PMID: 32823520 also summarises previously reported cases of KCND3-related SCA19. Patients can be split into early-onset and late-onset cohorts. In the early-onset group, neurodevelopmental disorder/cognitive impairment was the main finding (15/15), followed by ataxia 14/15, and epilepsy (7/15). Conversely, later-onset patients tend to first present with ataxia (50/53), with no epilepsy reported.

PMID: 32921676 Nakajima et al., 2020
Two teenage siblings exhibiting both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral phenotypes (epilepsy and intellectual disability), heterozygous for a KCND3 c.1174G>A p.(Val392Ile) mutation - not in gnomAD v4, Revel score = 0.84 Deleterious.
Proband, 19yo female III-1: (WISC-III, FIQ: 64 at 13yo - mild ID), episodes of focal impaired awareness seizures (from age 3 to 9) - focal spikes on EEG, brain MRI normal.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12yo – moderate ID); episodes of focal impaired awareness seizures (from age 2 to 7) - focal spikes on EEG, brain MRI normal. suddenly lost consciousness at home and died at 16 years of age, posed to be due to Early Repolarisation Syndrome.

Supporting evidence:
https://research.rug.nl/en/publications/molecular-genetics-of-monogenic-movement-disorders-making-meaning (internal PhD thesis)
International cohort (mostly European descent) of 21 patients with de novo missense variants in KCND3, aged 2-55 years. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.

Functional evidence: PMID: 39562497 Hung et al., 2025
A mouse model with a p.Phe227del-equivalent Kcnd3 knock-in displayed defects in motor coordination and balance, neuroinflammation, trafficking defect due to accumulation in the golgi apparatus, and a transcriptional effect: downregulation of genes involved in neurogenesis. Meanwhile, Kcnd3 knockout mice showed no observable phenotype. This evidence suggests a dominant negative effect of the mutation, and supports the association of KCND3 and neurodevelopmental disorders.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Sources: Literature

Created: 3 Oct 2025, 2:49 p.m. | Last Modified: 3 Oct 2025, 4:18 p.m.

Panel Version: 8.37

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Spinocerebellar ataxia 19 (OMIM: 607346); spinocerebellar ataxia type 19/22, MONDO:0011819

Publications

• 26189493
• 28947073
• 32823520
• 32921676
• 39562497