Activity

Filter

Cancel
Date Panel Item Activity
17 actions
Early onset or syndromic epilepsy v8.139 KCND3 Arina Puzriakova Tag dd_review was removed from gene: KCND3.
Tag Q3_25_promote_green was removed from gene: KCND3.
Early onset or syndromic epilepsy v8.134 KCND3 Achchuthan Shanmugasundram reviewed gene: KCND3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v8.134 KCND3 Arina Puzriakova Source NHS GMS was added to KCND3.
Source Expert Review Green was added to KCND3.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v8.38 KCND3 Eleanor Williams Tag dd_review tag was added to gene: KCND3.
Tag Q3_25_promote_green tag was added to gene: KCND3.
Early onset or syndromic epilepsy v8.38 KCND3 Eleanor Williams Classified gene: KCND3 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v8.38 KCND3 Eleanor Williams Added comment: Comment on list classification: Promoting to amber with a recommendation for green rating following GMS review.
Early onset or syndromic epilepsy v8.38 KCND3 Eleanor Williams Gene: kcnd3 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska edited their review of gene: KCND3: Changed publications to: 26189493, 28947073, 32823520, 32921676, 39562497
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska changed review comment from: 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. Thus, based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.; to: 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.
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska changed review comment from: 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. Thus, based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.; to: 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. Thus, based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska changed review comment from: 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.

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; to: 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
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska commented on gene: KCND3: 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. Thus, based on the available evidence, this gene should be rated Green for Early onset or syndromic epilepsy.
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska edited their review of gene: KCND3: Changed publications to: 26189493, 28947073, 32823520, 32921676
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska changed review comment from: 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: 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.

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; to: 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.

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
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska changed review comment from: 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: 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 13 years of age - mild ID), episodes of focal impaired awareness seizures.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12 years of age – moderate ID); episodes of focal impaired awareness seizures; 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.

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; to: 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: 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.

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
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska changed review comment from: 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 childhood onset epilepsy:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents. Het for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) not in gnomAD v4.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability, epilepsy, attention deficit hyperactivity disorder, strabismus, oral apraxia and joint hyperlaxity. Sequencing method: WES.
Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID, speech difficulties; suffered from focal and generalised motor seizures.
Brain MRI at age 23 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 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).

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 13 years of age - mild ID), episodes of focal impaired awareness seizures.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12 years of age – moderate ID); episodes of focal impaired awareness seizures; 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. All 21 patients had developmental delay and developed a mild to profound intellectual disability. Cerebellar ataxia was present in 11/21 patients. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.

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; to: 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: 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 13 years of age - mild ID), episodes of focal impaired awareness seizures.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12 years of age – moderate ID); episodes of focal impaired awareness seizures; 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.

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
Early onset or syndromic epilepsy v8.37 KCND3 Ida Ertmanska gene: KCND3 was added
gene: KCND3 was added to Early onset or syndromic epilepsy. Sources: Literature
Mode of inheritance for gene: KCND3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCND3 were set to 26189493; 28895081; 32823520; 31293010; 32921676
Phenotypes for gene: KCND3 were set to Spinocerebellar ataxia 19 (OMIM: 607346); spinocerebellar ataxia type 19/22, MONDO:0011819
Review for gene: KCND3 was set to GREEN
Added comment: 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 childhood onset epilepsy:

PMID: 26189493 Smets et al., 2015
Male patient, Belgian, non-consanguineous parents. Het for a de novo KCND3 mutation c.877_885dup; p.(Arg293_Phe295dup) not in gnomAD v4.
Phenotype: early onset cerebellar ataxia complicated by intellectual disability, epilepsy, attention deficit hyperactivity disorder, strabismus, oral apraxia and joint hyperlaxity. Sequencing method: WES.
Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID, speech difficulties; suffered from focal and generalised motor seizures.
Brain MRI at age 23 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 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).

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 13 years of age - mild ID), episodes of focal impaired awareness seizures.
Younger sister III-2: ID (WISC-III, FIQ: 41 at 12 years of age – moderate ID); episodes of focal impaired awareness seizures; 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. All 21 patients had developmental delay and developed a mild to profound intellectual disability. Cerebellar ataxia was present in 11/21 patients. 10/21 patients experienced seizures, 8 diagnosed with epilepsy.

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