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| Intellectual disability v9.108 | KCND3 | Eleanor Williams Added comment: Comment on phenotypes: OMIM phenotype accessed on 5th October 2025 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v9.108 | KCND3 | Eleanor Williams Phenotypes for gene: KCND3 were changed from Spinocerebellar ataxia 19, 607346 to Spinocerebellar ataxia 19, OMIM: 607346; spinocerebellar ataxia type 19/22, MONDO:0011819 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v9.107 | KCND3 | Eleanor Williams Publications for gene: KCND3 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v9.106 | KCND3 | Eleanor Williams Classified gene: KCND3 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v9.106 | KCND3 | Eleanor Williams Added comment: 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v9.106 | KCND3 | Eleanor Williams Gene: kcnd3 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v9.105 | 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 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. Thus, based on the available evidence, this gene should be rated Amber for Intellectual disability.; to: 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. |
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| Intellectual disability v9.105 | KCND3 | Ida Ertmanska edited their review of gene: KCND3: Changed publications to: 26189493, 28895081, 32823520, 31293010, 32921676, 39562497 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v9.105 | 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 phenotypes. While there 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. Thus, based on the available evidence, this gene should be rated Amber for Intellectual disability.; to: 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. Thus, based on the available evidence, this gene should be rated Amber for Intellectual disability. |
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| Intellectual disability v9.105 | 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. As reviewed by Nour Elkhateeb, there are reports of individuals with early 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.; 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. 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. |
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| Intellectual disability v9.105 | KCND3 | Ida Ertmanska edited their review of gene: KCND3: Changed phenotypes to: Spinocerebellar ataxia 19 (OMIM: 607346), spinocerebellar ataxia type 19/22, MONDO:0011819 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v9.105 | 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 phenotypes. While there 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. Based on the available evidence, this gene should be rated Amber for Intellectual disability.; to: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there 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. Thus, based on the available evidence, this gene should be rated Amber for Intellectual disability. |
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| Intellectual disability v9.105 | 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 phenotypes. While there 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. Based on the available evidence, this gene should be rated Amber for Intellectual disability.; to: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there 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. Based on the available evidence, this gene should be rated Amber for Intellectual disability. |
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| Intellectual disability v9.105 | 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 phenotypes. While there 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. Based on the available evidence, this gene should be rated Amber for Intellectual disability.; to: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there 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. Based on the available evidence, this gene should be rated Amber for Intellectual disability. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v9.105 | 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 phenotypes. While there are at least 4 published reports of individuals with early onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/severe/profound ID. Additionally, their cognitive impairment may have developed as a result of seizures and cerebellar atrophy. Based on the available evidence, this gene should be rated Amber for Intellectual disability.; to: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there 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. Based on the available evidence, this gene should be rated Amber for Intellectual disability. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v9.105 | KCND3 | Ida Ertmanska edited their review of gene: KCND3: Changed publications to: 26189493, 28895081, 32823520, 31293010, 32921676 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v9.105 | 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. As reviewed by Nour Elkhateeb, there are reports of individuals with early 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: 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.; 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. As reviewed by Nour Elkhateeb, there are reports of individuals with early 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. |
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| Intellectual disability v9.105 | KCND3 | Ida Ertmanska edited their review of gene: KCND3: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v9.105 | KCND3 | Ida Ertmanska edited their review of gene: KCND3: Added comment: Comment on list classification: KCND3 is associated with autosomal dominant Spinocerebellar ataxia 19, with a range of variably penetrant phenotypes. While there are at least 4 published reports of individuals with early onset intellectual disability/ developmental delay, only 2 cases meet the eligibility criteria of moderate/severe/profound ID. Additionally, their cognitive impairment may have developed as a result of seizures and cerebellar atrophy. Based on the available evidence, this gene should be rated Amber for Intellectual disability.; Changed publications to: 26189493, 28895081, 32823520, 32921676 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v9.105 | KCND3 | Ida Ertmanska reviewed gene: KCND3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinocerebellar ataxia 19 (OMIM: 607346); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v9.99 | KCND3 | Nour Elkhateeb reviewed gene: KCND3: Rating: GREEN; Mode of pathogenicity: None; Publications: 32823520, 32921676, 26189493, 28895081, 40140957; Phenotypes: Developmental delay, intellectual disability, ataxia, Seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v3.421 | KCND3 |
Arina Puzriakova Source Expert Review Red was added to KCND3. Rating Changed from Amber List (moderate evidence) to Red List (low evidence) |
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| Intellectual disability v3.252 | KCND3 | Arina Puzriakova commented on gene: KCND3 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v3.0 | KCND3 | Zornitza Stark reviewed gene: KCND3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinocerebellar ataxia 19, MIM#607346; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability | KCND3 | BRIDGE consortium edited their review of KCND3 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability | KCND3 | BRIDGE consortium edited their review of KCND3 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability | KCND3 | Louise Daugherty classified KCND3 as amber | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability | KCND3 | Louise Daugherty commented on KCND3 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability | KCND3 | BRIDGE consortium reviewed KCND3 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||