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| Childhood onset dystonia, chorea or related movement disorder v7.17 | HCN2 | Ida Ertmanska Added comment: Comment on list classification: In a cohort of 21 patients with HCN2 variants (mono- and bi- allelic), 12 presented with movement disorders, including dystonia, tremor, cerebellar signs, and stereotypies. Hence, this gene should be promoted to Green on Childhood onset dystonia, chorea or related movement disorder with MOI BOTH monoallelic and biallelic, autosomal or pseudoautosomal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Childhood onset dystonia, chorea or related movement disorder v7.16 | HCN2 |
Ida Ertmanska gene: HCN2 was added gene: HCN2 was added to Childhood onset dystonia, chorea or related movement disorder. Sources: Literature Q1_26_promote_green tags were added to gene: HCN2. Mode of inheritance for gene: HCN2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: HCN2 were set to 40468825 Phenotypes for gene: HCN2 were set to Generalized epilepsy with febrile seizures plus, type 11, OMIM:602477; neurodevelopmental disorder, MONDO:0700092 Review for gene: HCN2 was set to GREEN Added comment: PMID: 40468825 Houdayer et al., 2025 21 individuals with HCN2 variants from 15 unrelated families - 13 monoallelic cases and 8 biallelic. The phenotypic spectrum included developmental delay/intellectual disability (DD/ID, 17/21), epilepsy (10/21), language disorders (16/21), movement disorders (12/21), and axial hypotonia (10/21). Movement disorders included dystonia, tremor, cerebellar signs, stereotypies. Muscle tone abnormalities included axial hypotonia, hypertonia, pyramidal signs and spasticity. Biallelic LOF cases uniformly presented with severe intellectual disability, while monoallelic cases showed mild to moderate ID (IQ 40-60) with evidence of skill regression. Heterozygous GOF variants resulted in borderline ID and milder epilepsy phenotype. Thirteen pathogenic HCN2 variants (12 new and 1 already described) were identified: 11 missense, 1 recurrent inframe deletion, and 1 frameshift. Functional evidence: electrophysiology with Xenopus laevis oocytes and membrane trafficking investigated in HEK cells - p.(Arg324His) variant showed a strong increase of HCN2 conductance; p.(Ala363Val) and p.(Met374Leu) exhibited dominant negative effects. The p.(Leu377His), p.(Pro493Leu), and p.(Gly587Asp) variants rendered HCN2 electrophysiologically silent and impaired membrane trafficking. Structural 3D-analysis revealed that, except for p.(Arg324His), all variants altered HCN2 stability. HCN2 is associated with several AD phenotypes in OMIM: Generalized epilepsy with febrile seizures plus, type 11 602477; Febrile seizures, familial, 2 602477; {Epilepsy, idiopathic generalized, susceptibility to, 17} 602477 - all same MIM number (accessed 12th Mar 2026). Not yet added to ClinGen or Gene2Phenotype. Sources: Literature |
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| Childhood onset dystonia, chorea or related movement disorder v3.38 | L2HGDH |
Achchuthan Shanmugasundram changed review comment from: PMID:15824270 - A 15 year-old boy with L-2-hydroxyglutaric aciduria was reported with early infantile-onset progressive psychomotor regression, mild choreodystonia affecting the distal part of the upper limbs, pyramidal signs, and epilepsy. PMID:18780161 - Of seven patients from three unrelated Tunisian families with L-2-hydroxyglutaric aciduria and with homozygous variants in L2HGDH gene, three patients from two different families had dystonia. PMID:24753671 - Two siblings were reported with dystonia diagnosed by classical neuroimaging findings with elevated urinary 2 hydroxyglutaric acid.; to: PMID:15824270 - A 15 year-old boy with L-2-hydroxyglutaric aciduria was reported with early infantile-onset progressive psychomotor regression, mild choreodystonia affecting the distal part of the upper limbs, pyramidal signs, and epilepsy. PMID:18780161 - Of seven patients from three unrelated Tunisian families with L-2-hydroxyglutaric aciduria and with homozygous variants in L2HGDH gene, three patients from two different families had dystonia. The age of onset of the disorder in these patients is around six years. PMID:24753671 - Two siblings (13 and 16 years of age with disease onset at 10 years of age) were reported with dystonia diagnosed by classical neuroimaging findings with elevated urinary 2 hydroxyglutaric acid. |
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| Childhood onset dystonia, chorea or related movement disorder v3.33 | SLC18A2 |
Achchuthan Shanmugasundram changed review comment from: PMID:23363473 - Eight children from an extended consanguineous Saudi Arabian family had a complex neurological disorder apparent since infancy. This disorder is characterised by abnormal movements, including parkinsonism, dystonia, and poor fine motor skills, as well as autonomic dysfunction, including abnormal sweating, cold extremities, and poor sleep. They were identified with a homozygous SLC18A2 variant (p.Pro387Leu). Functional evaluation showed that protein harbouring this variant has dramatically reduced activity than wild type protein, suggesting severe, but not complete loss of function as mechanism of action. PMID:26497564 - Two male siblings from a consanguineous fancy was reported with a disorder comprising truncal hypotonia, a general paucity of movements, extrapyramidal signs and cognitive delay. They were identified with a homozygous SLC18A2 variant (p.Pro237His).; to: PMID:23363473 - Eight children from an extended consanguineous Saudi Arabian family had a complex neurological disorder apparent since infancy. This disorder is characterised by abnormal movements, including parkinsonism, dystonia, and poor fine motor skills, as well as autonomic dysfunction, including abnormal sweating, cold extremities, and poor sleep. They were identified with a homozygous SLC18A2 variant (p.Pro387Leu). Functional evaluation showed that protein harbouring this variant has dramatically reduced activity than wild type protein, suggesting severe, but not complete loss of function as mechanism of action. PMID:26497564 - Two male siblings from a consanguineous family was reported with a disorder comprising truncal hypotonia, a general paucity of movements, extrapyramidal signs and cognitive delay. They were identified with a homozygous SLC18A2 variant (p.Pro237His). PMID:31240161 - A child from a consanguineous family presented with hypotonia, mental disability, epilepsy, uncontrolled movements, and gastrointestinal problems and was identified with a homozygous SLC18A2 variant (p.Pro316Ala). PMID:34078222 - A 6-month-old male infant who presented with developmental delay and suspected cerebral palsy was also diagnosed with infantile parkinsonism-dystonia-2 and was identified with the homozygous variant (p.Pro237His) reported in PMID:26497564. This gene has been associated with relevant phenotypes in OMIM (PMID:618049), but not in Gene2Phenotype. |
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| Childhood onset dystonia, chorea or related movement disorder v3.33 | SLC18A2 |
Achchuthan Shanmugasundram commented on gene: SLC18A2: PMID:23363473 - Eight children from an extended consanguineous Saudi Arabian family had a complex neurological disorder apparent since infancy. This disorder is characterised by abnormal movements, including parkinsonism, dystonia, and poor fine motor skills, as well as autonomic dysfunction, including abnormal sweating, cold extremities, and poor sleep. They were identified with a homozygous SLC18A2 variant (p.Pro387Leu). Functional evaluation showed that protein harbouring this variant has dramatically reduced activity than wild type protein, suggesting severe, but not complete loss of function as mechanism of action. PMID:26497564 - Two male siblings from a consanguineous fancy was reported with a disorder comprising truncal hypotonia, a general paucity of movements, extrapyramidal signs and cognitive delay. They were identified with a homozygous SLC18A2 variant (p.Pro237His). |
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| Childhood onset dystonia, chorea or related movement disorder v1.210 | ATP5G3 |
Zornitza Stark gene: ATP5G3 was added gene: ATP5G3 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Literature Mode of inheritance for gene: ATP5G3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ATP5G3 were set to 34636445; 34954817 Phenotypes for gene: ATP5G3 were set to Dystonia, early-onset, and/or spastic paraplegia, MIM# 619681 Review for gene: ATP5G3 was set to GREEN Added comment: Note that HGNC approved gene name is ATP5MC3. PMID: 34636445 reports a missense variant identified in a large single-family pedigree with dystonia and spastic paraplegia. The variant was identified via exome sequencing of the proband and a distant cousin, focussing on variants within the previously determined linkage region. The identical missense variant was also identified in a patient with childhood onset dystonic syndrome and was shown to be de novo. Functional studies of fibroblast cell lines from affected father (HSP) and proband of large family demonstrated decreased complex V function. A drosophila model containing the missense variant had reduced mobility and reduced complex V activity. PMID: 34954817 reports de novo monoallelic missense variants in three individuals, however one of these individuals was reported in above paper. The other two patients were: (1) a-15-year-old girl with milestone delay, pyramidal signs, and generalized dystonia with prominent upper-body involvement, and (2) a 6-year-old boy with delayed psychomotor development, lower-extremity spasticity, and elevated blood lactate levels Sources: Literature |
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| Childhood onset dystonia, chorea or related movement disorder v1.155 | IMPDH2 | Arina Puzriakova Added comment: Comment on list classification: This gene is not yet associated with a relevant phenotype in OMIM or G2P, but there are sufficient unrelated cases (3) presenting with signs of dystonia to rate as Green at the next GMS review. Other cases reported with motor dysfunction, and it is plausible that this may develop into dystonia later in life. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Childhood onset dystonia, chorea or related movement disorder v0.0 | GNS |
Ellen McDonagh gene: GNS was added gene: GNS was added to Childhood onset dystonia or chorea or related movement disorder. Sources: London North GLH,Expert Review Red Mode of inheritance for gene: GNS was set to |
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