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| Childhood onset dystonia, chorea or related movement disorder v3.65 | ASL |
Eleanor Williams changed review comment from: Argininosuccinic aciduria (ASA) is caused by homozygous mutation in the gene encoding argininosuccinate lyase (ASL). Onset is typically in the neonatal period or in late infancy. The association of biallelic variants in ASL and the phenotype of Argininosuccinic aciduria is well established. e.g. PMID: 12384776 - Linnebank et al 2002 - homozygous/compound het variants in ASL in 27 unrelated individuals of different ancestries. No phenotype information is given. They also found a complete homologue of this gene on chr 22 which is predicted to encode an immunoglobulin-lambda-like mRNA. PMID: 17326097 - Trevisson et al 2007 - report homozygous/compound het variants in ASL in 12 Italian patients with ASA. Ataxia is not mentioned as a phenotypic feature. PMID: 29326055 - AlTassan et al 2018 - a retrospective review of 54 Saudi Arabian patients with ASA from January 2000 to December 2015. 35 patients (63%) had genetic data available all with variants in the ASL gene; c.1060C > T; p.(Gln354*) in 26 patients (likely founder mutation); c.556C > T; p.(Arg186Trp) in 7 patients, c.602+1G > T in one patient and 1062+5G > C in one patient. 7/10 patients are reported to show spasticity although it is not reporterd whether they all shared the same founder variant in ASL. More recent retrospectives show that ataxia is reported in approx. 10% of individuals with Argininosuccinic aciduria. 2 cases with ataxia and ASL variant identified are reported. PMID: 38044746 - Gurung et al 2023 - conducted a UK national multicentre retrospective study assessing the movement disorder phenotype in ASA patients from July 2015 to June 2022. 60 patients were studied with a median age of 12.7 years (range: 6 months to 53 years). 17 (28%) individuals had ASA with neurodegenerative-related symptoms, movement disorder, hypotonia/fatigue and abnormal behaviour. Of these 4 were reported to show tremor/dystonia, with this phenotype present at ages 9, 11, 24 and 25 years of age. Homozygous or compound het ASL variants were recorded in 25/60 patients including 3 out of the 4 patients with tremor/dystonia (patients 4,9 and 25 with c.719-2A>G; c.857A>G, c.1153C>T; c.1153C>T and c.437G>A; c.446+1G>A respectively). Genotype data was not available for other patients. Although patient 4 from this study and patient 9 from the Baruteau et al 2017 study share the same genotype and are both male, their phenotypic descriptions differ so assuming here that they are not the same patient. PMID: 28251416 - Baruteau et al 2017 - conducted a retrospective and prospective analysis of patients in the UK with ASA from March 2013 - December 2015. Tremors or dystonia were reported in 4 individuals (1,4,9 and 25). All were diagnosed before the age of 3 although it is not stated at what age the tremors/dystonia were first noted. The first 3 of these patients had homozygous or compound het variants in ASL identified (c.35G>A;c.35G>A, c.377G>A;c.377G>A and c.719-2A>G, c.857A>G respectively). (PMID: 36994644 - Elkhateeb et al 2023 - characterise the incidence of epilepsy in patients with ASA. ); to: Argininosuccinic aciduria (ASA) is caused by homozygous mutation in the gene encoding argininosuccinate lyase (ASL). Onset is typically in the neonatal period or in late infancy. The association of biallelic variants in ASL and the phenotype of Argininosuccinic aciduria is well established. e.g. PMID: 12384776 - Linnebank et al 2002 - homozygous/compound het variants in ASL in 27 unrelated individuals of different ancestries, PMID: 17326097 - Trevisson et al 2007 - report homozygous/compound het variants in ASL in 12 Italian patients with ASA. PMID: 29326055 - AlTassan et al 2018 - a retrospective review of 54 Saudi Arabian patients with ASA from January 2000 to December 2015. 35 patients (63%) had genetic data available all with variants in the ASL gene; c.1060C > T; p.(Gln354*) in 26 patients (likely founder mutation); c.556C > T; p.(Arg186Trp) in 7 patients, c.602+1G > T in one patient and 1062+5G > C in one patient. More recent retrospectives show that tremors and/or dystonia is reported in some individuals with Argininosuccinic aciduria. 6 cases with ataxia and ASL variant identified are reported. PMID: 38044746 - Gurung et al 2023 - conducted a UK national multicentre retrospective study assessing the movement disorder phenotype in ASA patients from July 2015 to June 2022. 60 patients were studied with a median age of 12.7 years (range: 6 months to 53 years). 17 (28%) individuals had ASA with neurodegenerative-related symptoms, movement disorder, hypotonia/fatigue and abnormal behaviour. Of these 4 were reported to show tremor/dystonia, with this phenotype present at ages 9, 11, 24 and 25 years of age. Homozygous or compound het ASL variants were recorded in 25/60 patients including 3 out of the 4 patients with tremor/dystonia (patients 4,9 and 25 with c.719-2A>G; c.857A>G, c.1153C>T; c.1153C>T and c.437G>A; c.446+1G>A respectively). Genotype data was not available for other patients. Although patient 4 from this study and patient 9 from the Baruteau et al 2017 study share the same genotype and are both male, their phenotypic descriptions differ so assuming here that they are not the same patient. PMID: 28251416 - Baruteau et al 2017 - conducted a retrospective and prospective analysis of patients in the UK with ASA from March 2013 - December 2015. Tremors or dystonia were reported in 4 individuals (1,4,9 and 25). All were diagnosed before the age of 3 although it is not stated at what age the tremors/dystonia were first noted. The first 3 of these patients had homozygous or compound het variants in ASL identified (c.35G>A;c.35G>A, c.377G>A;c.377G>A and c.719-2A>G, c.857A>G respectively). (PMID: 36994644 - Elkhateeb et al 2023 - characterise the incidence of epilepsy in patients with ASA. ) |
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| Childhood onset dystonia, chorea or related movement disorder v3.22 | SLC30A9 |
Achchuthan Shanmugasundram gene: SLC30A9 was added gene: SLC30A9 was added to Childhood onset dystonia, chorea or related movement disorder. Sources: Literature Mode of inheritance for gene: SLC30A9 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC30A9 were set to 28334855; 34716203; 37041080 Phenotypes for gene: SLC30A9 were set to Birk-Landau-Perez syndrome, OMIM:617595 Review for gene: SLC30A9 was set to GREEN Added comment: PMID:28334855 - Six patients from a large multigenerational Bedouin kindred had onset of different combinations of intellectual disability, muscle weakness, oculomotor apraxia, and nephropathy in early childhood and they were identified with a homozygous variant in SLC30A9 gene (c.1047_1049delGCA; p.A350del). The age of onset of movement disorder was around 1-2 years of age. PMID:34716203 - A girl of African-American descent was identified with compound heterozygous variants in SLC30A9 gene (c.40delA & c.86_87dupCC) and was reported with a cerebrorenal syndrome. She presented around one year of age with microcephaly and global developmental delay. She also had bilateral sensorineural hearing loss and later developed dystonic movements affecting the whole body (onset was around 5-10 years of age). PMID:37041080 - Eight individuals from four unrelated families were reported with SLC30A9-related disease and they presented with intellectual disability and progressive hyperkinetic movement disorder, associated with oculomotor apraxia and ptosis despite phenotypic variability. The two families of British Pakistani descent harboured homozygous c.1253G>T (p.Gly418Val) variant, Egyptian Palestinian family harboured homozygous c.1049delCAG (pAla350del) variant, while family of European Australian descent had compound heterozygous variants (c.1083dup/ p.Val362Cysfs*5, and c.1413A>G/ p.Ser471=). The age of onset of movement disorder in these patients ranged from around 1-2 years to 16 years of age. This gene has been associated with relevant phenotypes in OMIM (MIM #617595), but not yet in Gene2Phenotype. Sources: Literature |
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| Childhood onset dystonia, chorea or related movement disorder v3.18 | TMEM151A |
Achchuthan Shanmugasundram changed review comment from: PMID:34518509 - Nine individuals from three unrelated Chines families with paroxysmal kinesigenic dyskinesia (PKD) were identified with autosomal dominant variants in TMEM151A gene. In addition, 8 unrelated patients (isolated cases) with sporadic occurrence of PKD were also identified with heterozygous variants, of which three patients inherited variants from an unaffected parent, suggesting incomplete penetrance. The age of onset of symptoms ranged between 9 and 15 years. In addition, supporting mouse model and in vitro functional assays suggested loss of function as the mechanism of disease. PMID:34820915 - 29 PRRT2-negative Chinese patients from 25 families with PKD identified with 24 heterozygous variants in TMEM151A gene. The mean age of onset of symptoms was 12.93 years, with 13 patients reported with spontaneous remission of the disease around 21 years of age. PMID:35587630 - De novo missense variant in TMEM151A was identified in a French man with PKD and he presented with brief attacks of dystonia after 16 years of age. PMID:35707035 - Screening of patients with PRRT2-negative PKD and other movement disorders identified two novel variants in TMEM151A gene in two patients with PKD. PMID:35727387 - Heterozygous missense variant was identified in four affected members of a 3-generation Chinese family with PKD and the variant segregated with the disorder in the family. This gene has been associated with relevant phenotype in OMIM (MIM #620245), but not in Gene2Phenotype.; to: PMID:34518509 - Nine individuals from three unrelated Chines families with paroxysmal kinesigenic dyskinesia (PKD) were identified with autosomal dominant variants in TMEM151A gene. In addition, 8 unrelated patients (isolated cases) with sporadic occurrence of PKD were also identified with heterozygous variants, of which three patients inherited variants from an unaffected parent, suggesting incomplete penetrance. The age of onset of symptoms ranged between 9 and 15 years. In addition, supporting mouse model and in vitro functional assays suggested loss of function as the mechanism of disease. PMID:34820915 - 29 PRRT2-negative Chinese patients from 25 families with PKD identified with 24 heterozygous variants in TMEM151A gene. The mean age of onset of symptoms was 12.93 years, with 13 patients reported with spontaneous remission of the disease around 21 years of age. PMID:35587630 - De novo missense variant in TMEM151A was identified in a French man with PKD and he presented with brief attacks of dystonia after 16 years of age. PMID:35707035 - Screening of patients with PRRT2-negative PKD and other movement disorders identified two novel variants in TMEM151A gene in two patients with PKD. PMID:35727387 - Heterozygous missense variant was identified in four affected members of a 3-generation Chinese family with PKD and the variant segregated with the disorder in the family. PMID:36724570 - Three patients presenting with PKD were identified with different TMEM151A variants. This gene has been associated with relevant phenotype in OMIM (MIM #620245), but not in Gene2Phenotype. |
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| Childhood onset dystonia, chorea or related movement disorder v1.263 | ADAR |
Arina Puzriakova Added comment: Comment on mode of inheritance: Should be updated from biallelic only to both mono- and biallelic at the next GMS panel update. Dystonia is an established feature of AGS6 (MIM# 615010) associated with AR variants in this gene. Overall the AD condition (dyschromatosis symmetrica hereditaria, MIM# 127400) often presents with changes in skin pigmentation as the only sign of disease. However, there have also been reports of neurologic deficits including ID, developmental regression, brain calcification, seizures and dystonia in some affected individuals, particularly with the Gly1007Arg variant (PMID: 16225627; 16817193; 19017046). Although the penetrance of extracutaneous features is reduced, there is value in testing heterozygous ADAR variants on these panels to ensure syndromic cases are not missed if not tested in the context of the skin phenotype. |
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| Childhood onset dystonia, chorea or related movement disorder v1.261 | AP1S2 |
Arina Puzriakova changed review comment from: Comment on mode of inheritance: Review of literature did not reveal any confirmed affected females. Female carriers of AP1S2 variants are phenotypically normal and have mostly shown random X-inactivation. Huo et al., 2019 (PMID: 30714330) state that they identified a female patient (I-1) but this individual was not available for genetic testing and so it is unclear whether they harboured a variant on a one or both alleles. As no confirmed female cases have been reported and the allelic requirement remains elusive, the MOI should be set to the default XL (i.e. monoallelic in females may cause disease) as this will ensure that both mono and biallelic variants are picked up in females by the pipeline.; to: Comment on mode of inheritance: Review of literature did not reveal any confirmed affected females. Female carriers of AP1S2 variants are phenotypically normal and have mostly shown random X-inactivation. Huo et al., 2019 (PMID: 30714330) state that they identified a female patient (I-1) but this individual was not available for genetic testing and so it is unclear whether they harboured a variant on a one or both alleles. As it is not known definitively whether females require a variant on each allele of this gene in order to be affected, the MOI should be set to the default XL (i.e. monoallelic in females may cause disease). |
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| Childhood onset dystonia, chorea or related movement disorder v1.240 | HECW2 | Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to promote this gene to Green at the next GMS panel update. Motor dysfunction is a key feature in majority of cases and of all individuals aged 5 years or older, only 7/12 could walk, although often with limited capacity. Therefore, inclusion of HECW2 on this panel could present potential diagnostic benefit. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Childhood onset dystonia, chorea or related movement disorder v1.239 | HECW2 |
Arina Puzriakova gene: HECW2 was added gene: HECW2 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Literature Q3_22_rating tags were added to gene: HECW2. Mode of inheritance for gene: HECW2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: HECW2 were set to 27389779; 27334371; 34321324 Phenotypes for gene: HECW2 were set to Neurodevelopmental disorder with hypotonia, seizures, and absent language, OMIM:617268 Review for gene: HECW2 was set to GREEN Added comment: Acharya et al., 2022 (PMID: 34321324) released a review of 35 previously published and new unpublished cases harbouring HECW2 variants. Clinical characteristics in all individuals included ID/DD and hypotonia with or without spasticity. The review also highlighted motor coordination/movement deficits in 21/28 subjects (75%). Stereotypic movements were the most common (15) but dystonia (4) and chorea (3) are also reported. Sources: Literature |
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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 v1.198 | CLPB |
Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Biallelic' to 'Both mono- and biallelic' at the next GMS update. Association between biallelic variants and disease is well established, with at least 7 affected individuals reported with a movement disorder. Recently, Wortmann et al. 2021 (PMID: 34140661) published six unrelated individuals with one of four different de novo monoallelic missense variants in CLPB. The phenotype strongly overlapped with that observed in the recessive disease. Three individuals were nonambulatory and one was ambulatory but with a wide based gait and not able to run or jump. Some functional studies of heterozygous variants were performed. |
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| Childhood onset dystonia, chorea or related movement disorder v1.159 | AP1S2 |
Arina Puzriakova Added comment: Comment on mode of inheritance: Review of literature did not reveal any confirmed affected females. Female carriers of AP1S2 variants are phenotypically normal and have mostly shown random X-inactivation. Huo et al., 2019 (PMID: 30714330) state that they identified a female patient (I-1) but this individual was not available for genetic testing and so it is unclear whether they harboured a variant on a one or both alleles. As no confirmed female cases have been reported and the allelic requirement remains elusive, the MOI should be set to the default XL (i.e. monoallelic in females may cause disease) as this will ensure that both mono and biallelic variants are picked up in females by the pipeline. |
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| Childhood onset dystonia, chorea or related movement disorder v1.157 | EIF2AK2 | Arina Puzriakova edited their review of gene: EIF2AK2: Added comment: A further 6 families reported (PMID:33236446; 33866603) harbouring 3 different variants in this gene (including the first homozygous case). Clinical presentation was prominent in all cases for dystonia with onset in infancy or childhood, with subsequent generalisation. Additional clinical details are limited for the family described in PMID:33866603. However, in the remaining families detailed in PMID:33236446, 3 unrelated individuals additionally developed mild ID, spasticity, and brain MRI alterations; while the other 2 families (6 individuals) only had isolated dystonia.; Changed publications to: 32197074, 33236446, 33866603 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Childhood onset dystonia, chorea or related movement disorder v1.140 | ARFGEF3 |
Zornitza Stark gene: ARFGEF3 was added gene: ARFGEF3 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Literature Mode of inheritance for gene: ARFGEF3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ARFGEF3 were set to 33098801 Phenotypes for gene: ARFGEF3 were set to Dystonia Review for gene: ARFGEF3 was set to GREEN gene: ARFGEF3 was marked as current diagnostic Added comment: 3 unrelated individuals reported with variants in this gene and dystonia: 1 x de novo missense variant: c.6212T>C p.Met2071Thr, phenotype: infancy-onset generalized dystonia (isolated) 1x stop-gain variant c.1773T>G p.Tyr591* inherited from mosaic mother), phenotype: infancy-onset generalized dystonia (isolated) 1 x de novo missense variant (Gene Matcher) c.250A>C p.Met84Leu childhood-onset generalized dystonia (isolated) Sources: Literature |
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| Childhood onset dystonia, chorea or related movement disorder v1.126 | VPS16 | Arina Puzriakova commented on gene: VPS16: Penetrance for gene VPS16 was set from None to Incomplete - some variants transmitted from an unaffected parent and heterozygous LoF variants are observed in presumably healthy individuals in gnomAD | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Childhood onset dystonia, chorea or related movement disorder v1.100 | VPS41 | Zornitza Stark edited their review of gene: VPS41: Added comment: PMID 33764426: Additional 9 individuals from 5 unrelated families reported.; Changed rating: GREEN; Changed publications to: 32808683, 33764426; Set current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Childhood onset dystonia, chorea or related movement disorder v1.84 | MED27 |
Arina Puzriakova gene: MED27 was added gene: MED27 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Literature Q2_21_rating tags were added to gene: MED27. Mode of inheritance for gene: MED27 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MED27 were set to 33443317 Phenotypes for gene: MED27 were set to Intellectual disability; Axial hypotonia; Spasticity; Dystonia; Cerebellar hypoplasia; Cataracts; Epilepsy Review for gene: MED27 was set to GREEN Added comment: MED27 is currently not associated with any phenotype in OMIM (last edited on 08/03/2012), but is listed in Gene2Phenotype with a 'probable' disease confidence rating for 'MED27-related neurodevelopmental disorder' - PMID: 33443317 (2021) - 16 individuals from 11 families with a neurodevelopmental syndrome characterised by mild to profound GDD/ID (14/14), axial hypotonia (14/15), distal spasticity and dystonic movements (13/15), cerebellar hypoplasia (12/14), cataracts (10/15), epilepsy (9/15), and microcephaly (4/14). Exome sequencing revealed biallelic variants in the MED27 gene, including 3 recurrent variants found in 2 or more families with different background. Overall sufficient (>3) unrelated cases for inclusion if phenotypes are considered to be within the scope of this panel - most individuals presented dystonic movements, but only 2 sibs experienced generalised dystonia. Sources: Literature |
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| Childhood onset dystonia, chorea or related movement disorder v1.82 | VPS4A |
Arina Puzriakova Added comment: Comment on list classification: At least 5 different variants reported in 10 unrelated individuals with a comparable phenotype, including childhood onset dystonia in 9/10 cases. Pathogenicity is supported by functional data. There is enough evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag) |
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| Childhood onset dystonia, chorea or related movement disorder v1.81 | VPS4A |
Arina Puzriakova gene: VPS4A was added gene: VPS4A was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert Review for-review tags were added to gene: VPS4A. Mode of inheritance for gene: VPS4A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: VPS4A were set to 33186545; 33186543; 33460484 Phenotypes for gene: VPS4A were set to CIMDAG syndrome Review for gene: VPS4A was set to GREEN Added comment: Gene currently not associated with any phenotype in OMIM (last edited: 20/12/2019) or Gene2Phenotype. - PMID: 33186545 (2020) - Six unrelated individuals with de novo missense variants (c.850A>T, c.850A>G, c.616G>A) affecting the ATPase domain of VPS4A. Clinical features include severe DD and profound ID (6/6), hypotonia (5/6), microcephaly (6/6), dystonia (5/6), congenital cataracts (4/5), epilepsy (3/6), anaemia (3/6 - dyserythropoietic in 2), and structural brain abnormalities including cerebellar hypoplasia (5/6) or severe cerebral atrophy (1/6). Some functional data indicating a dominant-negative effect. - PMID: 33186543 (2020) - Three unrelated individuals with congenital dyserythropoietic anaemia, severe neurodevelopmental delay, and dystonia. Two patients harboured different de novo variants (c.850A>T, c.608G>A) in the ATPase domain, while the third had a homozygous alteration (c.83C>T) occurring in the N-terminal microtubule interacting and trafficking domain of VPS4A. The first two individuals congenital microcephaly with brain MRI showing white matter and cerebral volume loss, thin corpus callosum, and ponto-cerebellar atrophy. One individual also displayed a seizure disorder and congenital cataracts. The case with the biallelic variant presented with a milder hematologic phenotype and had macrocephaly (rather than microcephaly) and delayed white matter myelination. Functional studies support pathogenicity. - PMID: 33460484 (2021) - One child with a a severe neurodevelopmental disorder and congenital haemolytic anaemia but no overt sign of dyserythropoiesis, associated with a de novo variant (c.850A>T) in VPS4A. Other features include microcephaly (-2.5 SD), choreodystonic movements, and bilateral cataract. Brain MRI showed cerebral atrophy, thin dysplastic corpus callosum, basal ganglia atrophy, brainstem hypoplasia, cerebellar hypoplasia and dysplasia Sources: Expert Review |
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| Childhood onset dystonia, chorea or related movement disorder v1.73 | RNU7-1 |
Arina Puzriakova gene: RNU7-1 was added gene: RNU7-1 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Literature for-review tags were added to gene: RNU7-1. Mode of inheritance for gene: RNU7-1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RNU7-1 were set to 33230297 Phenotypes for gene: RNU7-1 were set to Aicardi–Goutières syndrome-like; Type I interferonopathy Review for gene: RNU7-1 was set to GREEN Added comment: Not associated with any phenotype in OMIM or Gene2Phenotype. - PMID: 33230297 (2020) - 16 individuals from 11 families with biallelic variants in the RNU7-1 gene. Clinical features were typical of Aicardi–Goutières syndrome, including spasticity, dystonia, epilepsy, peripheral neuropathy, brain calcification, mild skin involvement and delayed psychomotor development. Upregulated interferon signalling was detected in patient blood and fibroblasts. 4/12 variants were observed in 2 or more families - several from different ethnic backgrounds. 8 variants are recorded in gnomAD but at a frequency of ≤0.005, and no biallelic variants were identified in control populations. Some functional data showing a disturbance of histone RNA processing in patient-derived compared to control fibroblasts. Sources: Literature |
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| Childhood onset dystonia, chorea or related movement disorder v1.62 | VPS41 |
Zornitza Stark gene: VPS41 was added gene: VPS41 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Literature Mode of inheritance for gene: VPS41 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: VPS41 were set to 32808683 Phenotypes for gene: VPS41 were set to Dystonia; intellectual disability Review for gene: VPS41 was set to RED Added comment: Single individual reported with homozygous canonical splice site variant resulting in exon 7 skipping, and global developmental delay and generalized dystonia. He attained a few words and voluntary limb movements but never sat unsupported. He had pale optic discs and an axonal neuropathy. From 6 years of age, his condition began to deteriorate, with reduced motor abilities and alertness. An MRI of the brain showed atrophy of the superior cerebellar vermis and slimming of the posterior limb of the corpus callosum. VPS41 is component of the HOPS complex and other genes in the complex have been implicated in movement disorders. Sources: Literature |
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| Childhood onset dystonia, chorea or related movement disorder v1.62 | VPS16 |
Zornitza Stark gene: VPS16 was added gene: VPS16 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Literature Mode of inheritance for gene: VPS16 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: VPS16 were set to 32808683 Phenotypes for gene: VPS16 were set to Dystonia Review for gene: VPS16 was set to GREEN Added comment: 18 individuals reported with high-impact variants in VPS16 and a progressive early onset dystonia (median age 12 years, range 3–50 years), with prominent oromandibular, bulbar, cervical, and upper limb involvement. Progressive generalization ensued, although most remained ambulant, and only a minority (16%) lost the ability to walk in adulthood. Additional clinical features of mild to moderate intellectual disability and neuropsychiatric symptoms were present in approximately one‐third. In 4 individuals, magnetic resonance imaging (MRI) showed bilateral and symmetrical hypointensity of the globi pallidi and sometimes also the midbrain and dentate nuclei, suggestive of iron deposition. Mild generalized cerebral atrophy was also apparent in 4 individuals. Sources: Literature |
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| Childhood onset dystonia, chorea or related movement disorder v1.61 | YIF1B |
Arina Puzriakova gene: YIF1B was added gene: YIF1B was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list for-review tags were added to gene: YIF1B. Mode of inheritance for gene: YIF1B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: YIF1B were set to 32006098 Phenotypes for gene: YIF1B were set to Central hypotonia; Failure to thrive; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Spasticity; Abnormality of movement Review for gene: YIF1B was set to GREEN Added comment: - PMID: 32006098 - 6 individuals (from 5 families) with biallelic YIF1B truncating variants. Presenting features: hypotonia, failure to thrive, microcephaly (5/6), severe global DD and ID as well as features suggestive of a motor disorder including dystonia (5/6), spasticity (6/6), dyskinesia (5/5). Seizures were reported in 2 unrelated individuals (2/6). MRI abnormalities were observed in some with thin CC being a feature in 3. Affected individuals were found to be homozygous for truncating variants (4/5 families being consanguineous). The following 3 variants were identified (NM_001039672.2) : c.186dupT or p.Ala64fs / c.360_361insACAT or p.Gly121fs / c.598G>T or p.Glu200*. Yif1B KO mice demonstrate a disorganized Golgi architecture in pyramidal hippocampal neurons (Alterio et al 2015 - PMID: 26077767). Functional/network analysis of genes co-regulated with YIF1B based on available RNAseq data, suggest enrichment in genes important for nervous system development and function. Sources: Expert list |
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| Childhood onset dystonia, chorea or related movement disorder v1.51 | SYT1 |
Zornitza Stark gene: SYT1 was added gene: SYT1 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list Mode of inheritance for gene: SYT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SYT1 were set to 30107533 Phenotypes for gene: SYT1 were set to Baker-Gordon syndrome MIM#618218 Review for gene: SYT1 was set to GREEN gene: SYT1 was marked as current diagnostic Added comment: 4 out of 11 individuals with a de novo variant had dystonia as a feature of the phenotype. Sources: Expert list |
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| Childhood onset dystonia, chorea or related movement disorder v1.51 | SLC16A2 |
Zornitza Stark gene: SLC16A2 was added gene: SLC16A2 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list Mode of inheritance for gene: SLC16A2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: SLC16A2 were set to 31410843 Phenotypes for gene: SLC16A2 were set to Allan-Herndon-Dudley syndrome, MIM# 300523 Review for gene: SLC16A2 was set to GREEN gene: SLC16A2 was marked as current diagnostic Added comment: Allan-Herndon-Dudley syndrome (AHDS) is an X-linked condition characterized by severely impaired intellectual development, dysarthria, athetoid movements, muscle hypoplasia, and spastic paraplegia. There is large phenotypic interfamilial and intrafamilial variability. In a recent review of 24 affected individuals (PMID 31410843), 16 presented with profound developmental delay, three had severe intellectual disability with poor language and walking with an aid, four had moderate intellectual disability with language and walking abilities, and one had mild intellectual disability with hypotonia. Overall, eight had learned to walk, all had hypotonia, 17 had spasticity, 18 had dystonia, 12 had choreoathetosis, 19 had hypomyelination, and 10 had brain atrophy. Kyphoscoliosis (n=12), seizures (n=7), and pneumopathies (n=5) were the most severe complications. Sources: Expert list |
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| Childhood onset dystonia, chorea or related movement disorder v1.50 | HNRNPH1 |
Arina Puzriakova gene: HNRNPH1 was added gene: HNRNPH1 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Literature Mode of inheritance for gene: HNRNPH1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: HNRNPH1 were set to 29938792; 32335897 Phenotypes for gene: HNRNPH1 were set to HNRNPH1-related neurodevelopmental disorder Review for gene: HNRNPH1 was set to GREEN Added comment: Probable gene for HNRNPH1-related neurodevelopmental disorder in G2P, but currently not associated with any phenotype in OMIM (last edited on 21/07/2017). Two studies report de novo variants in 8 unrelated cases with a syndromic intellectual disability disorder. Clinical features included moderate-severe GDD/ID (7/7), abnormalities on brain MRI (8/8), ophthalmological abnormalities (7/8), short stature (6/8), and microcephaly (6/8). Movement manifestations were also observed - 3 individuals were non-ambulatory, while another 3 presented dystonia, one of whom also had ataxia, tremor, and wide‐based gait. Sources: Literature |
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| Childhood onset dystonia, chorea or related movement disorder v1.49 | IRF2BPL |
Zornitza Stark gene: IRF2BPL was added gene: IRF2BPL was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list Mode of inheritance for gene: IRF2BPL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: IRF2BPL were set to 30057031; 30166628 Phenotypes for gene: IRF2BPL were set to Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures, MIM# 618088 Review for gene: IRF2BPL was set to GREEN gene: IRF2BPL was marked as current diagnostic Added comment: PMID: 30057031 - 7 individuals with neurodevelopmental regression (5/7), progressive ataxia (5/7), seizures (7/7), spasticity (2/7), dystonia (3/7) and global devel delay (7/7). PTCs produced a more severe phenotype than missense. Onset was in childhood. Cerebellar changes also less frequently reported. PMID: 30166628 - 11 individuals with de novo PTCs with childhood neurological regression, epilepsy (7/11), hypotonia (5/11), dystonia (3/11), cerebellar atrophy (5/10). MRI showed CNS defects in 6/10 patients. Sources: Expert list |
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| Childhood onset dystonia, chorea or related movement disorder v1.49 | GRIN1 |
Zornitza Stark gene: GRIN1 was added gene: GRIN1 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list Mode of inheritance for gene: GRIN1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: GRIN1 were set to 29365063; 27164704; 27164704; 28051072 Phenotypes for gene: GRIN1 were set to Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, MIM# 614254; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive, MIM# 617820 Review for gene: GRIN1 was set to GREEN gene: GRIN1 was marked as current diagnostic Added comment: Over 20 individuals reported with de novo missense variants in GRIN1 and severe neurodevelopmental phenotype, comprising ID, seizures, and a movement disorder, in particular dystonia. Two families reported with bi-allelic variants: different mechanism postulated (LOF vs affecting channel functioning or hypomorphic alleles), parents were carriers and unaffected. Movement disorder, in particular dystonia also reported in bi-allelic cases. Sources: Expert list |
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| Childhood onset dystonia, chorea or related movement disorder v1.49 | GNB1 |
Zornitza Stark gene: GNB1 was added gene: GNB1 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list Mode of inheritance for gene: GNB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: GNB1 were set to 27108799; 30194818; 27668284; 31034681 Phenotypes for gene: GNB1 were set to Mental retardation, autosomal dominant 42, MIM# 616973 Review for gene: GNB1 was set to GREEN gene: GNB1 was marked as current diagnostic Added comment: Multiple reports of dystonia in this disorder. In a recent series of 18 individuals with de novo mutations, the most observed substitution affected the p.Ile80 residue in exon 6, with 28% of individuals carrying a variant at this residue. Dystonia and growth delay were observed more frequently in individuals carrying variants in this residue, suggesting a potential genotype-phenotype correlation. Sources: Expert list |
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| Childhood onset dystonia, chorea or related movement disorder v1.7 | EIF2AK2 |
Arina Puzriakova gene: EIF2AK2 was added gene: EIF2AK2 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Literature for-review tags were added to gene: EIF2AK2. Mode of inheritance for gene: EIF2AK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: EIF2AK2 were set to 32197074 Phenotypes for gene: EIF2AK2 were set to Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome, 618877 Review for gene: EIF2AK2 was set to GREEN Added comment: Association with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation reported in both OMIM and G2P (probable). PMID: 32197074 (2020) - Distinct de novo missense variants were identified in eight unrelated individuals who all share a notable phenotypic overlap of developmental delay, cognitive impairment, white matter alterations, dysarthria or lack of speech, and neurologic regression with febrile illness. Other variable features included hypotonia (7/8), hypertonia (7/8), ataxia (6/8), dystonia (5/8), tremor (3/8) and seizures (4/8). Functional data confirm reduced kinase activity compared to the wildtype protein product, and authors predict a dominant-negative effect. Sources: Literature |
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| Childhood onset dystonia, chorea or related movement disorder v0.121 | VAMP2 | Louise Daugherty changed review comment from: Comment on phenotypes: Phenotype from Salpietro et al. Am J Hum Genet. 2019 Apr 4;104(4):721-730) de novo mutations in 5 unrelated individuals phenotype neurodevelopmental disorder characterized by axial hypotonia (which had been present since birth), intellectual disability, and autistic features. More severe phenotype includes additional neurological features, including central visual impairment, hyperkinetic movement disorder, and epilepsy or electroencephalography abnormalities. ?Better on intellectual disability or neurodevelopmental panel. Needs clinical input.; to: Comment on phenotypes: Phenotype from Salpietro et al. Am J Hum Genet. 2019 Apr 4;104(4):721-730) de novo mutations in 5 unrelated individuals phenotype neurodevelopmental disorder characterized by axial hypotonia (which had been present since birth), intellectual disability, and autistic features. More severe phenotype includes additional neurological features, including central visual impairment, hyperkinetic movement disorder, and epilepsy or electroencephalography abnormalities | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Childhood onset dystonia, chorea or related movement disorder v0.121 | VAMP2 | Louise Daugherty Added comment: Comment on phenotypes: Phenotype from Salpietro et al. Am J Hum Genet. 2019 Apr 4;104(4):721-730) de novo mutations in 5 unrelated individuals phenotype neurodevelopmental disorder characterized by axial hypotonia (which had been present since birth), intellectual disability, and autistic features. More severe phenotype includes additional neurological features, including central visual impairment, hyperkinetic movement disorder, and epilepsy or electroencephalography abnormalities. ?Better on intellectual disability or neurodevelopmental panel. Needs clinical input. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Childhood onset dystonia, chorea or related movement disorder v0.0 | IDUA |
Ellen McDonagh gene: IDUA was added gene: IDUA was added to Childhood onset dystonia or chorea or related movement disorder. Sources: London North GLH,Expert Review Red Mode of inheritance for gene: IDUA was set to |
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