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Childhood onset dystonia, chorea or related movement disorder v3.70 HSD17B10 Arina Puzriakova changed review comment from: Comment on list classification: Upgrading from Red to Amber but there is sufficient evidence to promote this gene to Green at the next GMS panel update - choreoathetoid movements and dystonia can be reported features of HSD10 disease (PMID: 12555940; 22132097; 26950678; 31654490); to: Comment on list classification: Upgrading from Red to Amber but there is sufficient evidence to promote this gene to Green at the next GMS panel update - choreoathetoid movements and dystonia can be reported features of HSD10 disease (PMID: 12555940; 22132097; 26950678; 27295195; 31654490)
Childhood onset dystonia, chorea or related movement disorder v3.70 HSD17B10 Arina Puzriakova Added comment: Comment on list classification: Upgrading from Red to Amber but there is sufficient evidence to promote this gene to Green at the next GMS panel update - choreoathetoid movements and dystonia can be reported features of HSD10 disease (PMID: 12555940; 22132097; 26950678; 31654490)
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. )
Childhood onset dystonia, chorea or related movement disorder v3.60 SHQ1 Sarah Leigh commented on gene: SHQ1: SHQ1 variants are associated with Neurodevelopmental disorder with dystonia and seizures, OMIM:619922 and Dystonia 35, childhood-onset, OMIM:619921, but not with a phenotype in Gen2Phen. At least 10 SHQ1 variants have been reported (PMIDs: 29178645 34542157; 36810590; 36847845) in eight unrelated cases. The phenotypic features were dystonia (7/7 cases examined), hypotonia (6/7 cases examined), intellectual disability (7/8 cases examined), and seizures (in 4/6 cases and 2 further unrelated cases where remaining affected siblings did not have seizures (1/2 and 3/4)(PMID: 36847845).
Childhood onset dystonia, chorea or related movement disorder v3.53 ARX Sarah Leigh changed review comment from: A review by Eldar Dedic (Independent Clinical Genetics Consultant)
Kwong, et al. (2019, PMID: 31324350) presented a Chinese family with infantile epileptic dyskinetic encephalopathy. The whole-exome-sequencing revealed ARX c.989G>A (p.Arg330His) in 13 years of age affected proband (who also suffered from dystonia), as well as in his unaffected mother and sister. Proband also had a healthy older brother who did not carry the variant. The proband’s muscle whole mitochondrial DNA analysis did not show the presence of a pathogenic variant. - Please note that ARX c.989G>A (p.Arg330His) was absent from gnomAD v2.1.1 as of December 2021 Gorman, et al. (2018, PMID: 29778428) presented 2 years of age Ohtahara syndrome male case of Romanian origin. Whole-exome-sequencing revealed ARX c.1600G>C (p.Ala534Pro) variant in a patient (who also had dystonia) and in his healthy mother (who was a low-level mosaic). The proband was negative for chromosomal array testing and had a normal brain MRI. - Please note that ARX c.1600G>C (p.Ala534Pro) was absent from gnomAD v2.1.1 as of December 2021 Charzewska, et al. (2013, PMID: 23657928) presented a family with intellectual disability and dystonia. Sequencing of ARX revealed the presence of c.4A>T (p.Ser2Cys) variant in 4 affected males (including 2 who had onset of dystonia at 2nd day of life and 12 years of age, respectively) and in 5 female carriers. - Please note that ARX c.4A>T (p.Ser2Cys) was absent from gnomAD v2.1.1 as of December 2021 Breen, et al. (2018, PMID: 29343471) presented 12 years of age male case with intellectual disability and hand dystonia. The ARX c.426_458dup (p.Gly143_Ala153dup) variant has been reported in the proband, his cousin and maternal uncle from Pakistan, both of which had hand dystonia, as well as in his unaffected mother. The patient had whole-exome-sequencing as one of the previous tests carried out. - Please note that ARX c.426_458dup (p.Gly143_Ala153dup) was absent from gnomAD v2.1.1 as of December 2021; to: A review by Eldar Dedic (Independent Clinical Genetics Consultant):
Kwong, et al. (2019, PMID: 31324350) presented a Chinese family with infantile epileptic dyskinetic encephalopathy. The whole-exome-sequencing revealed ARX c.989G>A (p.Arg330His) in 13 years of age affected proband (who also suffered from dystonia), as well as in his unaffected mother and sister. Proband also had a healthy older brother who did not carry the variant. The proband’s muscle whole mitochondrial DNA analysis did not show the presence of a pathogenic variant. - Please note that ARX c.989G>A (p.Arg330His) was absent from gnomAD v2.1.1 as of December 2021 Gorman, et al. (2018, PMID: 29778428) presented 2 years of age Ohtahara syndrome male case of Romanian origin. Whole-exome-sequencing revealed ARX c.1600G>C (p.Ala534Pro) variant in a patient (who also had dystonia) and in his healthy mother (who was a low-level mosaic). The proband was negative for chromosomal array testing and had a normal brain MRI. - Please note that ARX c.1600G>C (p.Ala534Pro) was absent from gnomAD v2.1.1 as of December 2021 Charzewska, et al. (2013, PMID: 23657928) presented a family with intellectual disability and dystonia. Sequencing of ARX revealed the presence of c.4A>T (p.Ser2Cys) variant in 4 affected males (including 2 who had onset of dystonia at 2nd day of life and 12 years of age, respectively) and in 5 female carriers. - Please note that ARX c.4A>T (p.Ser2Cys) was absent from gnomAD v2.1.1 as of December 2021 Breen, et al. (2018, PMID: 29343471) presented 12 years of age male case with intellectual disability and hand dystonia. The ARX c.426_458dup (p.Gly143_Ala153dup) variant has been reported in the proband, his cousin and maternal uncle from Pakistan, both of which had hand dystonia, as well as in his unaffected mother. The patient had whole-exome-sequencing as one of the previous tests carried out. - Please note that ARX c.426_458dup (p.Gly143_Ala153dup) was absent from gnomAD v2.1.1 as of December 2021
Childhood onset dystonia, chorea or related movement disorder v3.53 ARX Sarah Leigh commented on gene: ARX: A review by Eldar Dedic (Independent Clinical Genetics Consultant)
Kwong, et al. (2019, PMID: 31324350) presented a Chinese family with infantile epileptic dyskinetic encephalopathy. The whole-exome-sequencing revealed ARX c.989G>A (p.Arg330His) in 13 years of age affected proband (who also suffered from dystonia), as well as in his unaffected mother and sister. Proband also had a healthy older brother who did not carry the variant. The proband’s muscle whole mitochondrial DNA analysis did not show the presence of a pathogenic variant. - Please note that ARX c.989G>A (p.Arg330His) was absent from gnomAD v2.1.1 as of December 2021 Gorman, et al. (2018, PMID: 29778428) presented 2 years of age Ohtahara syndrome male case of Romanian origin. Whole-exome-sequencing revealed ARX c.1600G>C (p.Ala534Pro) variant in a patient (who also had dystonia) and in his healthy mother (who was a low-level mosaic). The proband was negative for chromosomal array testing and had a normal brain MRI. - Please note that ARX c.1600G>C (p.Ala534Pro) was absent from gnomAD v2.1.1 as of December 2021 Charzewska, et al. (2013, PMID: 23657928) presented a family with intellectual disability and dystonia. Sequencing of ARX revealed the presence of c.4A>T (p.Ser2Cys) variant in 4 affected males (including 2 who had onset of dystonia at 2nd day of life and 12 years of age, respectively) and in 5 female carriers. - Please note that ARX c.4A>T (p.Ser2Cys) was absent from gnomAD v2.1.1 as of December 2021 Breen, et al. (2018, PMID: 29343471) presented 12 years of age male case with intellectual disability and hand dystonia. The ARX c.426_458dup (p.Gly143_Ala153dup) variant has been reported in the proband, his cousin and maternal uncle from Pakistan, both of which had hand dystonia, as well as in his unaffected mother. The patient had whole-exome-sequencing as one of the previous tests carried out. - Please note that ARX c.426_458dup (p.Gly143_Ala153dup) was absent from gnomAD v2.1.1 as of December 2021
Childhood onset dystonia, chorea or related movement disorder v3.50 ARFGEF3 Eleanor Williams changed review comment from: No phenotype in OMIM. Checked that the publication PMID:33098801 mentions this gene in the supplementary material (page 55) and the 3 cases reported by Zornitza Stark.; to: No phenotype in OMIM. Checked that the publication PMID:33098801 mentions this gene in the supplementary material (page 55) and the 3 cases reported by Zornitza Stark. Adding the gene-checked tag.
Childhood onset dystonia, chorea or related movement disorder v3.48 PDGFB Sarah Leigh edited their review of gene: PDGFB: Added comment: PDGFB variants are associated with Basal ganglia calcification, idiopathic, 5 (OMIM:615483). No phenotype has been associated with PDGFB in Gen2Phen. Although the age of onset for OMIM:615483 is in adulthood, PMID: 23913003 reports four unrelated cases where the age of onset is listed as childhood or 10 years of age.; Changed rating: GREEN
Childhood onset dystonia, chorea or related movement disorder v3.43 OCLN Sarah Leigh edited their review of gene: OCLN: Added comment: It would appear that there are no published reports of dystonia, chorea or related movement disorder in cases carrying OCLN variants (PMID:20727516;34704946;34573918;28386946).; Changed rating: RED; Changed publications to: 20727516, 34704946, 34573918, 28386946
Childhood onset dystonia, chorea or related movement disorder v3.43 OCLN Sarah Leigh Added comment: Comment on list classification: To date, there are no reports of dystonia, chorea or other movement disorders associated with OCLN variants (PMID: 20727516;34704946;34573918;28386946). Therefore this gene should not be green on this panel.
Childhood onset dystonia, chorea or related movement disorder v3.42 KCNQ2 Sarah Leigh Added comment: Comment on list classification: There is only one case (PMID:12742592), of dystonia in a patient carrying a KCNQ2 variant. To date, there are no reports of relevant chorea or other movement disorders associated with KCNQ2 variants (PMID: 22275249;22926866;23621294;31418850;35780567;33794528). Therefore this gene should not be green on this panel.
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.
Childhood onset dystonia, chorea or related movement disorder v3.35 SLC18A2 Achchuthan Shanmugasundram Phenotypes for gene: SLC18A2 were changed from Brain Dopamine Serotonin Vesicular Transport Disease (Other disorders of neurotransmitter metabolism); Vesicular monoamine transporter deficiency to ?Parkinsonism-dystonia, infantile, 2, OMIM:618049
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.
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).
Childhood onset dystonia, chorea or related movement disorder v3.33 TBC1D24 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are five unrelated cases reported with dystonia as a feature of the overall phenotype. Hence, this gene can be promoted to green rating at the next major update.
Childhood onset dystonia, chorea or related movement disorder v3.23 SLC30A9 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are six unrelated families with childhood onset dystonia or choreoathetosis reported with biallelic variants in this gene. Hence, this gene can be promoted to Green at the next major update.
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
Childhood onset dystonia, chorea or related movement disorder v3.21 TMEM151A Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence (more than 40 unrelated cases and supporting functional evidence) available in support of the association of this gene to PKD. Hence, this gene can be rated Green in the next major update.; to: Comment on list classification: There is sufficient evidence (more than 40 unrelated cases and supporting functional evidence) available in support of the association of this gene to PKD with onset in childhood/ adolescence. Hence, this gene can be rated Green in the next major update.
Childhood onset dystonia, chorea or related movement disorder v3.21 TMEM151A Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (more than 40 unrelated cases and supporting functional evidence) available in support of the association of this gene to PKD. Hence, this gene can be rated Green in the next major update.
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.
Childhood onset dystonia, chorea or related movement disorder v3.12 TSPOAP1 Sarah Leigh changed review comment from: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. At least TSPOAP1 three variants have been reported in three unrelated families. Family members carrying homozygous TSPOAP1 variants have dystonia, intellectual disability and cerebellar atrophy to varying degrees. Motor symptoms were apparent between 11 and 13 years of age for NM_004758: c.2449_2450delinsTG, p.Gln817* and c.538delG, p.Ala180Profs*8, while NM_004758: c.5422G>A, p.Gly1808Ser was from 58 years through to the 60s. Similarly, cognitive impairment was apparent from school age and progressed to moderate to extensive, in the carries of the two terminating TSPOAP1 variants, while those with the missense variant were diagnosed with mild cognitive impairment (PMID: 33539324). In vitro functional studies and mouse models support the association of the TSPOAP1 variants and phenotypes seen in the cases (PMID: 33539324).; to: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. At least three TSPOAP1variants have been reported in three unrelated families. Family members carrying homozygous TSPOAP1 variants have dystonia, intellectual disability and cerebellar atrophy to varying degrees. Motor symptoms were apparent between 11 and 13 years of age for NM_004758: c.2449_2450delinsTG, p.Gln817* and c.538delG, p.Ala180Profs*8, while NM_004758: c.5422G>A, p.Gly1808Ser was from 58 years through to the 60s. Similarly, cognitive impairment was apparent from school age and progressed to moderate to extensive, in the carries of the two terminating TSPOAP1 variants, while those with the missense variant were diagnosed with mild cognitive impairment (PMID: 33539324). In vitro functional studies and mouse models support the association of the TSPOAP1 variants and phenotypes seen in the cases (PMID: 33539324).
Childhood onset dystonia, chorea or related movement disorder v3.12 TSPOAP1 Sarah Leigh changed review comment from: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. At least TSPOAP1 three variants have been reported in three unrelated families. Family members carrying homozygous TSPOAP1 variants have dystonia, intellectual disability and cerebellar atrophy to varying degrees (PMID: 33539324). In vitro functional studies and mouse models support the association of the TSPOAP1 variants and phenotypes seen in the cases (PMID: 33539324).; to: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. At least TSPOAP1 three variants have been reported in three unrelated families. Family members carrying homozygous TSPOAP1 variants have dystonia, intellectual disability and cerebellar atrophy to varying degrees. Motor symptoms were apparent between 11 and 13 years of age for NM_004758: c.2449_2450delinsTG, p.Gln817* and c.538delG, p.Ala180Profs*8, while NM_004758: c.5422G>A, p.Gly1808Ser was from 58 years through to the 60s. Similarly, cognitive impairment was apparent from school age and progressed to moderate to extensive, in the carries of the two terminating TSPOAP1 variants, while those with the missense variant were diagnosed with mild cognitive impairment (PMID: 33539324). In vitro functional studies and mouse models support the association of the TSPOAP1 variants and phenotypes seen in the cases (PMID: 33539324).
Childhood onset dystonia, chorea or related movement disorder v3.12 TSPOAP1 Sarah Leigh edited their review of gene: TSPOAP1: Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. At least TSPOAP1 three variants have been reported in three unrelated families. Family members carrying homozygous TSPOAP1 variants have dystonia, intellectual disability and cerebellar atrophy to varying degrees (PMID: 33539324). In vitro functional studies and mouse models support the association of the TSPOAP1 variants and phenotypes seen in the cases (PMID: 33539324).; Changed rating: GREEN
Childhood onset dystonia, chorea or related movement disorder v3.11 NUP54 Achchuthan Shanmugasundram changed review comment from: PMID:36333996 reported three unrelated patients with early-onset dystonia with striatal lesions identified with biallelic variants in NUP54 gene. One patient (patient A) had homozygous variant c.1073T>G (p.Ile358Ser), while other two patients had compound heterozygous variants (patient B: c.1073T>G (p.Ile358Ser) & c.1126A>G (p.Lys376Glu); patient C: c.1410_1412del (p.Gln471del) and two missense variants c.1414G>A (p.Glu472Lys) & c.1420C>T (p.Leu474Phe)).

The age of onset was between 12 months and five years and all had progressive neurological deterioration with dystonia, ataxia, dysarthria, dysphagia, hypotonia.

This gene has been associated with relevant phenotypes in Gene2Phenotype (NUP54-related early-onset dystonia with striatal lesions with 'moderate' rating in the DD panel), but not in OMIM.
Sources: Literature; to: PMID:36333996 reported three unrelated patients with early-onset dystonia with striatal lesions identified with biallelic variants in NUP54 gene. One patient (patient A) had homozygous variant c.1073T>G (p.Ile358Ser), while other two patients had compound heterozygous variants (patient B: c.1073T>G (p.Ile358Ser) & c.1126A>G (p.Lys376Glu); patient C: c.1410_1412del (p.Gln471del) and two missense variants c.1414G>A (p.Glu472Lys) & c.1420C>T (p.Leu474Phe)).

The age of onset was between 12 months and five years and all had progressive neurological deterioration with dystonia, ataxia, dysarthria, dysphagia, hypotonia.

Western blots showed reduced expression of NUP54 and its interaction partners NUP62/NUP58 in patient fibroblasts.

This gene has been associated with relevant phenotypes in Gene2Phenotype (NUP54-related early-onset dystonia with striatal lesions with 'moderate' rating in the DD panel), but not in OMIM.
Sources: Literature
Childhood onset dystonia, chorea or related movement disorder v3.10 NUP54 Achchuthan Shanmugasundram gene: NUP54 was added
gene: NUP54 was added to Childhood onset dystonia, chorea or related movement disorder. Sources: Literature
Mode of inheritance for gene: NUP54 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP54 were set to 36333996
Phenotypes for gene: NUP54 were set to Early-onset dystonia
Review for gene: NUP54 was set to GREEN
Added comment: PMID:36333996 reported three unrelated patients with early-onset dystonia with striatal lesions identified with biallelic variants in NUP54 gene. One patient (patient A) had homozygous variant c.1073T>G (p.Ile358Ser), while other two patients had compound heterozygous variants (patient B: c.1073T>G (p.Ile358Ser) & c.1126A>G (p.Lys376Glu); patient C: c.1410_1412del (p.Gln471del) and two missense variants c.1414G>A (p.Glu472Lys) & c.1420C>T (p.Leu474Phe)).

The age of onset was between 12 months and five years and all had progressive neurological deterioration with dystonia, ataxia, dysarthria, dysphagia, hypotonia.

This gene has been associated with relevant phenotypes in Gene2Phenotype (NUP54-related early-onset dystonia with striatal lesions with 'moderate' rating in the DD panel), but not in OMIM.
Sources: Literature
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.
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).
Childhood onset dystonia, chorea or related movement disorder v1.261 STUB1 Sarah Leigh Added comment: Comment on mode of inheritance: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. Numerous STUB1 variants have been reported in both Autosomal recessive spinocerebellar ataxia type 16, OMIM:615768 and Spinocerebellar ataxia 48, OMIM:618093. PMIDs 34906452; 35493319 report digenic occurrence of heterozygous STUB1 variants, with TBP_CAG expansions of 41-46. They question the validy of Spinocerebellar ataxia 48 (OMIM:618093) as a condition and whether it should be included into Spinocerebellar ataxia 17 (OMIM:607136).
Childhood onset dystonia, chorea or related movement disorder v1.258 DNAJC6 Dmitrijs Rots gene: DNAJC6 was added
gene: DNAJC6 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Literature
Mode of inheritance for gene: DNAJC6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAJC6 were set to 34175496
Review for gene: DNAJC6 was set to AMBER
Added comment: Ray et al. in 34175496 summarized reported cases with DNAJC6 - 6/6 studies had childhood-onset movement disorder (mostly parkinsonism) and homozygous variant (nonsense, splice, frameshift and missense).
Sources: Literature
Childhood onset dystonia, chorea or related movement disorder v1.257 XK Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. Numerous variants have been reported in cases of McLeod syndrome with or without chronic granulomatous disease (OMIM:300842), including at least two cases in females; severe symptoms were apparent in the index case (11.1) who had marked skewed X-inactivation favouring the wild type allele (PMID: 8619554).
After consultation with Helen Brittain (Clinical Fellow, Genomics England) it has been concluded that it is not appropriate for XK to be green on the Childhood onset dystonia or chorea or related movement disorder panel, as the phenotype is not evident in childhood, but rather from the 4th decade of life (PMIDs: 11761473;8004674;11032622;11261514;33652783;30128557), therefore, variants in XK would be predictive of possible future conditions.; to: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. Numerous variants have been reported in cases of McLeod syndrome with or without chronic granulomatous disease (OMIM:300842), including at least two cases in females; severe symptoms were apparent in the index case (11.1) who had marked skewed X-inactivation favouring the wild type allele (PMID: 8619554).
After consultation with Helen Brittain (Clinical Fellow, Genomics England) it has been concluded that it is not appropriate for XK to be green on the Childhood onset dystonia or chorea or related movement disorder panel, as the phenotype is not evident in childhood, but rather from the 4th decade of life (PMIDs: 11761473;8004674;11032622;11261514;33652783;30128557), therefore, variants in XK could be predictive of possible future conditions.
Childhood onset dystonia, chorea or related movement disorder v1.257 XK Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. Numerous variants have been reported in cases of McLeod syndrome with or without chronic granulomatous disease (OMIM:300842), including at least two cases in females; severe symptoms were apparent in the index case (11.1) who had marked skewed X-inactivation favouring the wild type allele (PMID: 8619554).; to: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. Numerous variants have been reported in cases of McLeod syndrome with or without chronic granulomatous disease (OMIM:300842), including at least two cases in females; severe symptoms were apparent in the index case (11.1) who had marked skewed X-inactivation favouring the wild type allele (PMID: 8619554).
After consultation with Helen Brittain (Clinical Fellow, Genomics England) it has been concluded that it is not appropriate for XK to be green on the Childhood onset dystonia or chorea or related movement disorder panel, as the phenotype is not evident in childhood, but rather from the 4th decade of life (PMIDs: 11761473;8004674;11032622;11261514;33652783;30128557), therefore, variants in XK would be predictive of possible future conditions.
Childhood onset dystonia, chorea or related movement disorder v1.248 ATP5G3 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Zornitza Stark (Australian Genomics). There is sufficient evidence to rate this gene as Green at the next GMS panel update - at least four unrelated families with heterozygous variants primarily presenting with dystonia or related movement disorder (PMID: 34636445; 34954817); also supportive Drosophila model described.
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
Childhood onset dystonia, chorea or related movement disorder v1.237 MAL Julia Baptista gene: MAL was added
gene: MAL was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Literature
Mode of inheritance for gene: MAL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAL were set to 35217805
Phenotypes for gene: MAL were set to developmental delay; nystagmus; progressive motor deterioration; dysmyelination
Review for gene: MAL was set to AMBER
Added comment: Single consanguineous family reported with two affected children (DD and nystagmus). New onset ataxia and cerebellar volume loss with patchy dysmyelination. Homozygous missense variant identified by exome analysis segregated with the condition. Functional data suggested that p.(Ala109Asp) severely affects protein folding of MAL, leading to mislocalization in the ER.
Sources: Literature
Childhood onset dystonia, chorea or related movement disorder v1.237 VPS4A Arina Puzriakova changed review comment from: Comment on mode of inheritance: Setting MOI to 'Monoallelic' as only one biallelic case reported to date, and patients with biallelic variants would still be picked up by the Genomics England pipeline.; to: Comment on mode of inheritance: Setting MOI to 'Monoallelic' as only one biallelic case reported to date. Added 'watchlist_moi tag to allow monitoring for additional cases.
Childhood onset dystonia, chorea or related movement disorder v1.235 SNORD118 Sarah Leigh edited their review of gene: SNORD118: Added comment: Associated with relevant phenotype in OMIM and as both RD and IF Gen2Phen gene. Numervous variants have been reported in cases with Leukoencephalopathy, brain calcifications, and cysts (OMIM:614561), which include features of motor involvement (PMID: 33029936).; Changed rating: GREEN
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
Childhood onset dystonia, chorea or related movement disorder v1.207 TARS2 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 11 variants reported in at least 7 unrelated cases with a varied phenotype, including encephalomyopathy, epilepsy, dystonia, hyperhidrosis and severe hearing impairment. Supportive functional studies were also presented PMID: 34508595.; to: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 11 variants reported in at least 7 unrelated cases with a varied phenotype, including encephalomyopathy, epilepsy, dystonia, hyperhidrosis and severe hearing impairment. At least three unrelated cases of dystonia reported. Supportive functional studies were also presented PMID: 34508595.
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.
Childhood onset dystonia, chorea or related movement disorder v1.193 NOP56 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: NOP56.
Tag currently-ngs-unreportable tag was added to gene: NOP56.
Childhood onset dystonia, chorea or related movement disorder v1.190 PPP2R2B Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: PPP2R2B.
Tag currently-ngs-unreportable tag was added to gene: PPP2R2B.
Childhood onset dystonia, chorea or related movement disorder v1.188 HTT Arina Puzriakova Added comment: Comment on mode of inheritance: Biallelic SNVs have been reported for Lopes-Maciel-Rodan syndrome
Childhood onset dystonia, chorea or related movement disorder v1.180 C9orf72_GGGGCC Arina Puzriakova Phenotypes for STR: C9orf72_GGGGCC were changed from Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 OMIM:105550; frontotemporal dementia and/or amyotrophic lateral sclerosis 1 MONDO:0007105 to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, OMIM:105550
Childhood onset dystonia, chorea or related movement disorder v1.179 C9orf72 Arina Puzriakova Phenotypes for gene: C9orf72 were changed from Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 OMIM:105550; frontotemporal dementia and/or amyotrophic lateral sclerosis 1 MONDO:0007105 to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, OMIM:105550
Childhood onset dystonia, chorea or related movement disorder v1.177 ATXN1 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATXN1.
Tag currently-ngs-unreportable tag was added to gene: ATXN1.
Childhood onset dystonia, chorea or related movement disorder v1.173 ATXN7 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATXN7.
Tag currently-ngs-unreportable tag was added to gene: ATXN7.
Childhood onset dystonia, chorea or related movement disorder v1.170 ATXN10 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATXN10.
Tag currently-ngs-unreportable tag was added to gene: ATXN10.
Childhood onset dystonia, chorea or related movement disorder v1.166 ATN1 Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: ATN1.
Tag currently-ngs-unreportable tag was added to gene: ATN1.
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.
Childhood onset dystonia, chorea or related movement disorder v1.157 SHQ1 Zornitza Stark gene: SHQ1 was added
gene: SHQ1 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Literature
Mode of inheritance for gene: SHQ1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHQ1 were set to 34542157; 29178645
Phenotypes for gene: SHQ1 were set to Dystonia; Neurodegeneration
Review for gene: SHQ1 was set to AMBER
Added comment: Three unrelated families reported. Family 1: isolated dystonia only; Family 2: dystonia, and neurodegeneration; Family 3: neurodegeneration.

Functional data in PMID 34542157

Rated Amber as phenotypes likely represent a continuum but currently unclear.
Sources: Literature
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 v1.155 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 v1.154 IMPDH2 Arina Puzriakova edited their review of gene: IMPDH2: Added comment: Kuukasjärvi et al., 2021 (PMID: 34305140) report on an additional large Finnish family (6 affected members) with a heterozygous truncating variant co-segregating with a dominantly inherited dystonia-tremor phenotype. Patient fibroblasts showed reduced IMPDH2 expression. IMPDH2 is the rate-limiting enzyme in the biosynthesis of guanine nucleotides, a dopamine synthetic pathway previously linked to childhood or adolescence-onset dystonia disorders.; Changed publications to: 33098801, 34305140
Childhood onset dystonia, chorea or related movement disorder v1.147 GNB1 Sarah Leigh edited their review of gene: GNB1: Added comment: Hemati et al (2018)(PMID: 30194818) reviewed 46 pathognic GNB1 variants in cases with Mental retardation, autosomal dominant 42 (OMIM:616973). They reported early hypotonia leading to hypertonia and spasticity in >75% of cases.; Changed rating: GREEN
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
Childhood onset dystonia, chorea or related movement disorder v1.136 DMPK Arina Puzriakova changed review comment from: Comment on list classification: Demoted from Green to Red due to the disease-causing mechanism - genetic defect is an amplified trinucleotide CTG repeat in the 3'UTR (currently NGS unreportable), rather than SNVs within the gene. Evidence level for this is high - it is a confirmed DD gene for DYSTROPHIA MYOTONICA TYPE 1.; to: Comment on list classification: Demoted from Amber to Red due to the disease-causing mechanism - genetic defect is an amplified trinucleotide CTG repeat in the 3'UTR (currently NGS unreportable), rather than SNVs within the gene. Evidence level for this is high - it is a confirmed DD gene for DYSTROPHIA MYOTONICA TYPE 1.
Childhood onset dystonia, chorea or related movement disorder v1.136 DMPK Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: DMPK.
Tag currently-ngs-unreportable tag was added to gene: DMPK.
Childhood onset dystonia, chorea or related movement disorder v1.135 DMPK Arina Puzriakova Added comment: Comment on list classification: Demoted from Green to Red due to the disease-causing mechanism - genetic defect is an amplified trinucleotide CTG repeat in the 3'UTR (currently NGS unreportable), rather than SNVs within the gene. Evidence level for this is high - it is a confirmed DD gene for DYSTROPHIA MYOTONICA TYPE 1.
Childhood onset dystonia, chorea or related movement disorder v1.126 VPS16 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 19 unrelated families reported with progressive dystonia (both multifocal and generalised types described) in association with variants in this gene (publications updated with relevant literature). Variable age of onset ranging from 3 to 50 years.
Childhood onset dystonia, chorea or related movement disorder v1.122 FOXG1 Sarah Leigh edited their review of gene: FOXG1: Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. All of the patients with FOXG1 variants reported in PMID 27029630 abnormal involuntary movements, including chorea/athetosis in 22/25 (88%) cases.; Changed rating: GREEN
Childhood onset dystonia, chorea or related movement disorder v1.110 C9orf72_GGGGCC Sarah Leigh Phenotypes for STR: C9orf72_GGGGCC were changed from Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 105550 to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 OMIM:105550; frontotemporal dementia and/or amyotrophic lateral sclerosis 1 MONDO:0007105
Childhood onset dystonia, chorea or related movement disorder v1.109 C9orf72 Sarah Leigh Phenotypes for gene: C9orf72 were changed from Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 105550 to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 OMIM:105550; frontotemporal dementia and/or amyotrophic lateral sclerosis 1 MONDO:0007105
Childhood onset dystonia, chorea or related movement disorder v1.106 C9orf72_GGGGCC Sarah Leigh STR: C9orf72_GGGGCC was added
STR: C9orf72_GGGGCC was added to Childhood onset dystonia or chorea or related movement disorder. Sources: NHS GMS,Expert Review Green,London North GLH,Expert list
STR tags were added to STR: C9orf72_GGGGCC.
Mode of inheritance for STR: C9orf72_GGGGCC was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for STR: C9orf72_GGGGCC were set to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 105550
Childhood onset dystonia, chorea or related movement disorder v1.103 GLRB Sarah Leigh edited their review of gene: GLRB: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least four variants reported in three unrelated cases.; Changed rating: GREEN
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 v1.96 FITM2 Sarah Leigh edited their review of gene: FITM2: Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least four variants reported in at least three unrelated cases. Supportive drosophila model.; Changed rating: GREEN
Childhood onset dystonia, chorea or related movement disorder v1.94 SCN1A Sarah Leigh edited their review of gene: SCN1A: Added comment: A non-Dravet syndrome epileptic encephalopathy phenotype associated with SCN1A variants. Eight cases carriers of p.Thr226Met shared this non-typical phenotype. This phenotype is not represented in OMIM, but they have been notified of the reporting publication (PMID 28794249), additional phenotype may be added to OMIM in the future.; Changed rating: GREEN
Childhood onset dystonia, chorea or related movement disorder v1.83 VPS4A Arina Puzriakova Added comment: Comment on mode of inheritance: Setting MOI to 'Monoallelic' as only one biallelic case reported to date, and patients with biallelic variants would still be picked up by the Genomics England pipeline.
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)
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
Childhood onset dystonia, chorea or related movement disorder v1.77 TOR1A Arina Puzriakova Phenotypes for gene: TOR1A were changed from Autosomal dominant or sporadic dystonia (DYT1); Early-Onset Primary Dystonia; Dystonia-1, torsion, 128100 to Dystonia-1, torsion, OMIM:128100; Dystonic disorder, MONDO:0003441
Childhood onset dystonia, chorea or related movement disorder v1.76 CACNB4 Sarah Leigh edited their review of gene: CACNB4: Added comment: PMID 10762541 reports monoallelic variants associated with Idiopathic Generalized Epilepsy and Episodic Ataxia and PMID 32176688 reports biallelic variants associated with severe neurodevelopmental disorder and impairs channel and non-channel functions. Therefore recommend the MOI be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Childhood onset dystonia, chorea or related movement disorder v1.74 CACNB4 Sarah Leigh commented on gene: CACNB4: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. At least 3 variants reported in at least 3 unrelated cases, together with supportive functional data.
Childhood onset dystonia, chorea or related movement disorder v1.74 RNU7-1 Arina Puzriakova Added comment: Comment on list classification: Rating Amber but should be promoted to Green at the next GMS panel update (added 'for-review' tag) - spastic dystonia was a feature in 9/16 patients (7 families) reported with biallelic variants in this gene (PMID:33230297)
Childhood onset dystonia, chorea or related movement disorder v1.72 B9D2 Arina Puzriakova Publications for gene: B9D2 were set to 26092869 - two further cases with Joubert syndrome reported from two different families; 21763481 - two affected fetuses form the same family displayed overlapping phenotypes including cystic kidneys, ductal plate malformation, polydactyly, and occipital encephalocele. Homozygous variant identified in this gene, which was not present in the unaffected son. Homozygous variants were not identified in other known Meckel syndrome genes
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
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
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
Childhood onset dystonia, chorea or related movement disorder v1.51 TBC1D24 Zornitza Stark gene: TBC1D24 was added
gene: TBC1D24 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list
Mode of inheritance for gene: TBC1D24 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D24 were set to 31257402
Phenotypes for gene: TBC1D24 were set to Epilepsy, rolandic, with proxysmal exercise-induce dystonia and writer's cramp, MIM# 608105
Review for gene: TBC1D24 was set to GREEN
Added comment: Three unrelated families reported with rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp (EPRPDC), an autosomal recessive neurologic disorder characterised by onset of focal seizures in infancy and exercise-induced dystonia in childhood. Features usually include involuntary movements, including facial movements, and difficulties with fine motor skills of the hand. Seizures often respond to medication and remit with age; the dystonia tends to persist. Three unrelated families reported with this specific phenotype, though variants in this gene are associated with a range of other neurological disorders and may represent a spectrum of severity.
Sources: Expert list
Childhood onset dystonia, chorea or related movement disorder v1.51 SNORD118 Zornitza Stark gene: SNORD118 was added
gene: SNORD118 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list
Mode of inheritance for gene: SNORD118 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNORD118 were set to 27571260
Phenotypes for gene: SNORD118 were set to Leukoencephalopathy, brain calcifications, and cysts MIM#614561
Review for gene: SNORD118 was set to GREEN
Added comment: At least 6 cases/families reported with dystonia as a feature of the condition.
Sources: Expert list
Childhood onset dystonia, chorea or related movement disorder v1.51 HNRNPH1 Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - two studies report de novo variants in at least 6 unrelated cases with a movement phenotype.
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
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
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
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
Childhood onset dystonia, chorea or related movement disorder v1.49 FITM2 Zornitza Stark gene: FITM2 was added
gene: FITM2 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: Expert list
Mode of inheritance for gene: FITM2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FITM2 were set to 28067622; 30214770; 30288795
Phenotypes for gene: FITM2 were set to Siddiqi syndrome MIM#618635; dystonia; deafness
Review for gene: FITM2 was set to GREEN
gene: FITM2 was marked as current diagnostic
Added comment: 7 cases from 3 unrelated families (2 consanguineous) with a dystonia-deafness syndrome and a supporting Drosophila model.
Sources: Expert list
Childhood onset dystonia, chorea or related movement disorder v1.49 C9orf72 Zornitza Stark reviewed gene: C9orf72: Rating: RED; Mode of pathogenicity: None; Publications: 26166205, 24363131, 26187722; Phenotypes: Frontotemporal dementia and/or amyotrophic lateral sclerosis 1, MIM# 105550; Mode of inheritance: None
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
Childhood onset dystonia, chorea or related movement disorder v0.258 TPK1 Louise Daugherty Added comment: Comment on list classification: Changed from Red to Green as per recommendation from Specialist Test Group (via Robyn Labrum LNGLH). Reported in multiple families
Childhood onset dystonia, chorea or related movement disorder v0.256 ACTB Louise Daugherty changed review comment from: Comment on list classification: Changed from Amber to Green as per recommendation from Specialist Test Group (via Robyn Labrum LNGLH).
Despite the evidence in the literature not supporting a Green rating the Specialist Test Group still supported a Green rating based on limited evidence – juvenile onset dystonia, only identified in 1 family, twins, brains examined post mortem; to: Comment on list classification: Changed from Amber to Green as per recommendation from Specialist Test Group (via Robyn Labrum LNGLH) 12 December 2019.
Despite the evidence in the literature not supporting a Green rating the Specialist Test Group still supported a Green rating based on limited evidence – juvenile onset dystonia, only identified in 1 family, twins, brains examined post mortem
Childhood onset dystonia, chorea or related movement disorder v0.256 ACTB Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green as per recommendation from Specialist Test Group (via Robyn Labrum LNGLH).
Despite the evidence in the literature not supporting a Green rating the Specialist Test Group still supported a Green rating based on limited evidence – juvenile onset dystonia, only identified in 1 family, twins, brains examined post mortem
Childhood onset dystonia, chorea or related movement disorder v0.119 GNAL Louise Daugherty changed review comment from: Comment on list classification: downgraded until Specialist Test Group review - need more evidence; to: Comment on list classification: downgraded until Specialist Test Group review rating in view of age of onset Average age at onset 31 years (range 7 to 54)

Monoallelic mutations have been associated with adult-onset cranio-cervical dystonia - PMID: 23222958 (more than 2 families with adult onset of focal dystonia (plus plus neck), which often progresses to involve other regions), 23449625 (4 families with reduced penetrance, adult onset of focal dystonia), 23759320 (2 chinese families and sporadic adult onset generalized dystonia), 24151159 (3 sporadic cases with adult-onset dystonia involving the neck and or face), 24408567 (1 sporadic case adult-onset dystonia), 24535567 (2 families with craniocervical dystonia), 24729450 (1 sporadic cervical dystonia, DE NOVO), 25382112 (2 sporadic with dystonia) plus other similar publications. ONE BIALLELIC MUTATION described in 27222887 1 girl from cons parents with generalised dystonia and mild ID.
Childhood onset dystonia, chorea or related movement disorder v0.115 SLC6A3 Louise Daugherty Phenotypes for gene: SLC6A3 were changed from {Nicotine dependence, protection against}, 188890; Dopamine transporter deficiency; Parkinsonism-dystonia, infantile, 613135 to Dopamine transporter deficiency; Parkinsonism-dystonia, infantile, 613135
Childhood onset dystonia, chorea or related movement disorder v0.32 C9orf72 Ellen McDonagh Phenotypes for gene: C9orf72 were changed from to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 105550
Childhood onset dystonia, chorea or related movement disorder v0.23 TPK1 Ellen McDonagh Added comment: Comment on list classification: Kept as Red, as only one patient reported with dystonia, and one Red review.
Childhood onset dystonia, chorea or related movement disorder v0.9 ACTB Ellen McDonagh Added comment: Comment on list classification: Promoted from Red to Amber, as there has only been one variant reported.
Childhood onset dystonia, chorea or related movement disorder v0.7 TOR1A Ellen McDonagh Source PanelApp was added to TOR1A.
Mode of inheritance for gene TOR1A was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Added phenotypes Autosomal dominant or sporadic dystonia (DYT1); Early-Onset Primary Dystonia; Dystonia-1, torsion, 128100 for gene: TOR1A
Publications for gene TOR1A were changed from to 20301334; 11523564; 17503336; 20301665; 9288096; 16537570
Childhood onset dystonia, chorea or related movement disorder v0.7 CHMP2B Ellen McDonagh Source PanelApp was added to CHMP2B.
Mode of inheritance for gene CHMP2B was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Added phenotypes Frontotemporal dementia and/or amyotrophic lateral sclerosis 1; Dystonia; familial frontotemporal lobar degeneration (ALS17) for gene: CHMP2B
Childhood onset dystonia, chorea or related movement disorder v0.7 SLC6A3 Ellen McDonagh Source PanelApp was added to SLC6A3.
Mode of inheritance for gene SLC6A3 was changed from to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes {Nicotine dependence, protection against}, 188890; Dopamine transporter deficiency; Parkinsonism-dystonia, infantile, 613135 for gene: SLC6A3
Publications for gene SLC6A3 were changed from to 21112253; 27830117; 24613933
Childhood onset dystonia, chorea or related movement disorder v0.7 SLC18A2 Ellen McDonagh Source PanelApp was added to SLC18A2.
Mode of inheritance for gene SLC18A2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes Brain Dopamine Serotonin Vesicular Transport Disease (Other disorders of neurotransmitter metabolism); Vesicular monoamine transporter deficiency for gene: SLC18A2
Publications for gene SLC18A2 were changed from to 27830117; 28477711; 26497564; 23363473; 27520881; 24398404; 24018103; 27604308
Childhood onset dystonia, chorea or related movement disorder v0.7 HYLS1 Ellen McDonagh Source PanelApp was added to HYLS1.
Mode of inheritance for gene HYLS1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes Joubert syndrome; Hydrolethalus syndrome, 236680 for gene: HYLS1
Publications for gene HYLS1 were changed from to 18648327 - Hydrolethalus syndrome; 19656802 - impairment in ciligenesis; 15843405 - Hydrolethalus syndrome; 26830932 - report in two siblings with Joubert syndrome
Childhood onset dystonia, chorea or related movement disorder v0.7 FOLR1 Ellen McDonagh Source PanelApp was added to FOLR1.
Mode of inheritance for gene FOLR1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes Neurodegeneration due to cerebral folate transport deficiency, 613068; Folate receptor alpha deficiency for gene: FOLR1
Publications for gene FOLR1 were changed from to 27830117; 21937992; 19732866; 2044715
Childhood onset dystonia, chorea or related movement disorder v0.7 B9D2 Ellen McDonagh Source PanelApp was added to B9D2.
Mode of inheritance for gene B9D2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes Meckel syndrome; Joubert syndrome; Meckel syndrome 10, 614175; ciliopathies for gene: B9D2
Publications for gene B9D2 were changed from to 26092869 - two further cases with Joubert syndrome reported from two different families; 21763481 - two affected fetuses form the same family displayed overlapping phenotypes including cystic kidneys, ductal plate malformation, polydactyly, and occipital encephalocele. Homozygous variant identified in this gene, which was not present in the unaffected son. Homozygous variants were not identified in other known Meckel syndrome genes
Childhood onset dystonia, chorea or related movement disorder v0.1 TREM2 Ellen McDonagh gene: TREM2 was added
gene: TREM2 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: South West GLH
Mode of inheritance for gene: TREM2 was set to
Phenotypes for gene: TREM2 were set to Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2, 618193; Alzheimers disease; Frontotemporal dementia
Childhood onset dystonia, chorea or related movement disorder v0.1 PSEN1 Ellen McDonagh gene: PSEN1 was added
gene: PSEN1 was added to Childhood onset dystonia or chorea or related movement disorder. Sources: South West GLH
Mode of inheritance for gene: PSEN1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PSEN1 were set to Alzheimer disease, type 3, 607822; Pick disease, 172700; Dementia, frontotemporal 600274; Cardiomyopathy, dilated, 1U, 613694
Childhood onset dystonia, chorea or related movement disorder v0.0 POR Ellen McDonagh gene: POR was added
gene: POR was added to Childhood onset dystonia or chorea or related movement disorder. Sources: London North GLH,Expert Review Red
Mode of inheritance for gene: POR was set to