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Intellectual disability

Gene: KCND3

Amber List (moderate evidence)
KCND3 (potassium voltage-gated channel subfamily D member 3)
EnsemblGeneIds (GRCh38): ENSG00000171385
EnsemblGeneIds (GRCh37): ENSG00000171385
OMIM: 605411, Gene2Phenotype
KCND3 is in 11 panels

8 reviews

Eleanor Williams (Genomics England Curator)

Comment on phenotypes: OMIM phenotype accessed on 5th October 2025
Created: 5 Oct 2025, 10:59 p.m. | Last Modified: 5 Oct 2025, 10:59 p.m.
Panel Version: 9.108
Comment on list classification: Promoting to amber as there are some cases with intellectual disability/cognitive impairment however this appears to be at the milder end of the phenotypic spectrum.
Created: 5 Oct 2025, 10:58 p.m. | Last Modified: 5 Oct 2025, 10:58 p.m.
Panel Version: 9.106
Created: 5 Oct 2025, 10:58 p.m.
Last Modified: 5 Oct 2025, 10:58 p.m.
Panel version: 9.106

Ida Ertmanska (Genomics England Curator)

I don't know

Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there are published articles with at least 6 individuals with early-onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/ severe/ profound ID. Additionally, the cognitive impairment may have developed as a result of seizures and cerebellar atrophy. Many patients with KCND3 mutations do not have any cognitive impariment.
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 Amber for Intellectual disability.
Created: 3 Oct 2025, 2:33 p.m. | Last Modified: 3 Oct 2025, 4:24 p.m.
Panel Version: 9.105
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. As reviewed by Nour Elkhateeb, there are reports of individuals with childhood onset intellectual disability / developmental delay:

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. Intellectual Disability diagnosed at 3yo. IQ = 54 at 6yo – mild. Sequencing method: WES.
Demonstrated pathogenic effect of variant in a patch clamp assay - severe Kv4.3 channel dysfunction.

PMID: 28895081 Kurihara et al., 2018
30-year-old Japanese man with intellectual disability (IQ = 59, mild), infantile onset developmental delay, early onset cerebellar ataxia, myoclonus, and dystonia without a family history. MRI showed cerebellar atrophy.
Carried a de novo novel missense mutation c.1150G>A, p.(Gly384Ser) in KCND3 – Revel score = 0.88 Deleterious, variant not in gnomAD v4; seq method: trio WES.

PMID: 31293010 Hsiao et al., 2019
Patient A.III-1 - Male, 24 yo - developmental delay, ataxia (since 15yo), MMSE score 12/30, brain atrophy reported. Het for c.950G>A, p.(Cys317Tyr) - Revel = 0.97, not in gnomAD v4.
Patient B.II-2 - Male, 39yo, cognitive impairment (first symptom), ataxia since age 10-15, dystonia, bradykinesia, MMSE score 14/30, brain atrophy reported. Het for c.1123C>T, p.(Pro375Ser) - Revel = 0.95, not in gnomAD v4.

PMID: 32823520 Pollini et al. 2020
Case report, 37yo male, mild ID (onset at 5 yo), IQ=67, speech difficulties; suffered from focal and generalised motor seizures; At age 7yo, IQ = 41 - secondary effect of seizures/brain atrophy?
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.
Patient 14 (United States): IQ = 44 at 13yo - c.1111G>A p.(Gly371Arg) / de novo; variant not in gnomAD v4, Revel = 0.99.
Patient 16 (Netherlands): IQ = 45 at 9yo, 25 at 12yo - c.1123C>T p.(Pro375Ser)/de novo; variant not in gnomAD v4, Revel = 0.95.
Patient 4 (Netherlands): Developmental age of 10-11 m at age 44 m; ‘Severe ID’, regression; c.917G>T p.(Gly306Val)/de novo; variant not in gnomAD v4, Revel = 0.97.

KCND3 is associated with Spinocerebellar ataxia 19 (OMIM:607346, accessed 3rd Oct 2025). Based on the available evidence, this gene should be rated Amber for Intellectual Disability.
Created: 3 Oct 2025, 2:14 p.m. | Last Modified: 3 Oct 2025, 2:44 p.m.
Panel Version: 9.105

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

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

Publications

Created: 3 Oct 2025, 2:14 p.m.
Last Modified: 3 Oct 2025, 4:24 p.m.
Panel version: 9.105

Nour Elkhateeb (Cambridge University Hospitals NHS Foundation Trust)

Green List (high evidence)

Recent evidence of an early onset neurodevelopmental phenotype with neurodevelopmental difficulties, ID, ataxia and epilepsy. Examples include (PMID: 32823520, 32921676, 26189493, 28895081, 40140957, https://doi.org/10.1212/WNL.98.18_supplement.2361)
Created: 26 Sep 2025, 8:32 a.m. | Last Modified: 26 Sep 2025, 8:32 a.m.
Panel Version: 9.99

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Developmental delay; intellectual disability; ataxia; Seizures

Publications

Created: 26 Sep 2025, 8:32 a.m.
Last Modified: 26 Sep 2025, 8:32 a.m.
Panel version: 9.99

Arina Puzriakova (Genomics England Curator)

Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza Stark
Created: 17 Aug 2020, 10:01 a.m. | Last Modified: 17 Aug 2020, 10:01 a.m.
Panel Version: 3.252
Created: 17 Aug 2020, 10:01 a.m.
Last Modified: 17 Aug 2020, 10:01 a.m.
Panel version: 3.252

Zornitza Stark (Australian Genomics)

Red List (low evidence)

Progressive neurological condition; ID only reported in some, most however reported as having normal cognition.
Created: 8 Feb 2020, 9:10 a.m. | Last Modified: 8 Feb 2020, 9:10 a.m.
Panel Version: 3.0

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Spinocerebellar ataxia 19, MIM#607346

Created: 8 Feb 2020, 9:10 a.m.
Last Modified: 8 Feb 2020, 9:10 a.m.
Panel version: 3.0

Olivia Niblock (Genomics England Curator)

I don't know

Should be amber - two cases of spinocerebellar ataxia with intellectual disability, however, many other cases with variants in this gene but no intellectual disability described.
Created: 31 Oct 2017, 10:36 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Created: 31 Oct 2017, 10:36 a.m.

Panel version: Imported from Intellectual disability update Oct 2017 panel version 0.6

BRIDGE consortium (NIHRBR-RD)

Green List (high evidence)

This is a pertinent gene from the NIHR BioResource - Rare Diseases Study (NIHRBR-RD) BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene is on the SPEED_NEURO_20170705 gene list. Evidences used for SPEED NEURO gene list: in_omim_20150205_movement . Main mutation mechanism : NA
Created: 27 Jul 2017, 6:59 p.m.
Evidences key, gene present in following gene lists and main mutation mechanism : omim_20150205_movement; neuro_20160418_strict; NA. This is a pertinent gene from the BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene comes from the SPEED_NEURO_v3.0_20170404 gene list. The following experts from the BRIDGE consortium NIHRBR-RD contributed to this panel: - Professor F. Lucy Raymond, Cambridge Institute for Medical Research, University of Cambridge - Manju Kurian, Paediatric neurologist, Great Ormond Street Hosptial - Keren Carss, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Alba Sanchis-Juan, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Marie Erwood NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Louise Daugherty, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust
Created: 19 Jul 2017, 12:42 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Publications

  • omim.org

Created: 2 Aug 2017, 7:37 p.m.

Panel version: 1.354

Louise Daugherty (Genomics England Curator)

Comment on list classification: This gene is from an expert list and needs further assessment by the Genomics England curation team to assess inclusion and pertinence to this panel.
Created: 20 Jul 2017, 12:08 p.m.
Created: 20 Jul 2017, 12:08 p.m.

Panel version: 1.206

History Filter Activity

5 Oct 2025, Gel status: 2

Set Phenotypes

Eleanor Williams (Genomics England Curator)

Phenotypes for gene: KCND3 were changed from Spinocerebellar ataxia 19, 607346 to Spinocerebellar ataxia 19, OMIM: 607346; spinocerebellar ataxia type 19/22, MONDO:0011819

5 Oct 2025, Gel status: 2

Set publications

Eleanor Williams (Genomics England Curator)

Publications for gene: KCND3 were set to

5 Oct 2025, Gel status: 2

Entity classified by Genomics England curator

Eleanor Williams (Genomics England Curator)

Gene: kcnd3 has been classified as Amber List (Moderate Evidence).

12 Oct 2020, Gel status: 1

Added New Source, Status Update

Arina Puzriakova (Genomics England Curator)

Source Expert Review Red was added to KCND3. Rating Changed from Amber List (moderate evidence) to Red List (low evidence)

12 Mar 2018, Gel status: 2

Panel promoted to version 2.0

Ellen McDonagh (Genomics England Curator)

12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.

20 Jul 2017, Gel status: 2

Gene classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

This gene has been classified as Amber List (Moderate Evidence).

19 Jul 2017, Gel status: 0

Created

BRIDGE consortium (NIHRBR-RD)

KCND3 was created by BRIDGE

19 Jul 2017, Gel status: 0

Added New Source

BRIDGE consortium (NIHRBR-RD)

KCND3 was added to Intellectual disabilitypanel. Sources: BRIDGE study SPEED NEURO Tier1 Gene