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Early-onset Parkinson disease v2.2 PSMF1 Zornitza Stark gene: PSMF1 was added
gene: PSMF1 was added to Early-onset Parkinson disease. Sources: Literature
Mode of inheritance for gene: PSMF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PSMF1 were set to https://www.medrxiv.org/content/10.1101/2024.06.19.24308302v1
Phenotypes for gene: PSMF1 were set to Complex neurodevelopmental disorder with motor features, MONDO:0100516, PSMF1-related
Review for gene: PSMF1 was set to GREEN
Added comment: 22 individuals from 15 families reported with a range of neurological phenotypes ranging from early-onset Parkinson's disease; childhood conditions typified by ID and a range of movement disorders; through to perinatal lethal presentations with arthrogryposis multiplex. Genotype-phenotype correlation: biallelic missense variants resulted in the milder phenotypes, while bi-allelic LoF variants in the more severe phenotypes. Supportive functional data.
Sources: Literature
Early-onset Parkinson disease v2.1 RAB32 Bryony Thompson changed review comment from: A single variant in RAB32 - c.213C>G p.(Ser71Arg) with a significant association with PD (odds ratio [OR] 13.17, 95% CI 2.15-87.23; p=0.0055, 6,043 PD cases and 62,549 controls).
The variant cosegregated with autosomal dominant PD in 3 families (9 affected individuals), with incomplete penetrance. In vitro studies demonstrate that RAB32 Ser71Arg activates LRRK2 kinase.
Sources: Literature; to: A single variant in RAB32 - c.213C>G p.(Ser71Arg) with a significant association with PD (odds ratio [OR] 13.17, 95% CI 2.15-87.23; p=0.0055, 6,043 PD cases and 62,549 controls).
The variant cosegregated with autosomal dominant PD in 3 families (9 affected individuals), with incomplete penetrance. In vitro studies demonstrate that RAB32 Ser71Arg activates LRRK2 kinase.
The variant is reported as a novel reduced penetrance PD risk factor. The 95% CI for the OR estimate are very wide. A confirmatory study is required for this variant.
Sources: Literature
Early-onset Parkinson disease v2.1 RAB32 Bryony Thompson edited their review of gene: RAB32: Changed rating: RED
Early-onset Parkinson disease v0.347 WDR45 Bryony Thompson Phenotypes for gene: WDR45 were changed from to X-linked complex neurodevelopmental disorder MONDO:0100148
Early-onset Parkinson disease v0.345 WDR45 Bryony Thompson Mode of inheritance for gene: WDR45 was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early-onset Parkinson disease v0.344 VPS13A Bryony Thompson Phenotypes for gene: VPS13A were changed from to chorea-acanthocytosis MONDO:0008695
Early-onset Parkinson disease v0.342 VPS13A Bryony Thompson Mode of inheritance for gene: VPS13A was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Parkinson disease v0.341 TUBB4A Bryony Thompson Mode of inheritance for gene: TUBB4A was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.339 TH Bryony Thompson Phenotypes for gene: TH were changed from to Tyrosine hydroxylase deficiency MONDO:0100064
Early-onset Parkinson disease v0.336 TH Bryony Thompson Mode of inheritance for gene: TH was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Parkinson disease v0.335 SPR Bryony Thompson Phenotypes for gene: SPR were changed from to Dopa-responsive dystonia due to sepiapterin reductase deficiency MONDO:0012994
Early-onset Parkinson disease v0.333 SPR Bryony Thompson Mode of inheritance for gene: SPR was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Parkinson disease v0.332 SLC30A10 Bryony Thompson Mode of inheritance for gene: SLC30A10 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Early-onset Parkinson disease v0.332 SLC30A10 Bryony Thompson Mode of inheritance for gene: SLC30A10 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Parkinson disease v0.330 SLC30A10 Bryony Thompson Phenotypes for gene: SLC30A10 were changed from to cirrhosis - dystonia - polycythemia - hypermanganesemia syndrome MONDO:0013208
Early-onset Parkinson disease v0.329 SPG11 Bryony Thompson Mode of inheritance for gene: SPG11 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Parkinson disease v0.328 SPG11 Bryony Thompson Phenotypes for gene: SPG11 were changed from hereditary spastic paraplegia 11 MONDO:0011445 to hereditary spastic paraplegia 11 MONDO:0011445
Early-onset Parkinson disease v0.327 SPG11 Bryony Thompson Phenotypes for gene: SPG11 were changed from hereditary spastic paraplegia 11 MONDO:0011445 to hereditary spastic paraplegia 11 MONDO:0011445
Early-onset Parkinson disease v0.327 SPG11 Bryony Thompson Phenotypes for gene: SPG11 were changed from to hereditary spastic paraplegia 11 MONDO:0011445
Early-onset Parkinson disease v0.326 RAB39B Bryony Thompson Mode of inheritance for gene: RAB39B was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early-onset Parkinson disease v0.324 RAB39B Bryony Thompson Phenotypes for gene: RAB39B were changed from to Early-onset parkinsonism-intellectual disability syndrome MONDO:0010709
Early-onset Parkinson disease v0.323 PSEN1 Bryony Thompson Mode of inheritance for gene: PSEN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.322 PSEN1 Bryony Thompson Mode of inheritance for gene: PSEN1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.320 PSEN1 Bryony Thompson Phenotypes for gene: PSEN1 were changed from to Alzheimer disease 3 MONDO:0011913
Early-onset Parkinson disease v0.319 PRKN Bryony Thompson Phenotypes for gene: PRKN were changed from to autosomal recessive juvenile Parkinson disease 2 MONDO:0010820
Early-onset Parkinson disease v0.318 PRKN Bryony Thompson Mode of inheritance for gene: PRKN was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Parkinson disease v0.317 PARK7 Bryony Thompson Phenotypes for gene: PARK7 were changed from to autosomal recessive early-onset Parkinson disease 7 MONDO:0011658
Early-onset Parkinson disease v0.315 PARK7 Bryony Thompson Mode of inheritance for gene: PARK7 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Parkinson disease v0.314 ANG Bryony Thompson Marked gene: ANG as ready
Early-onset Parkinson disease v0.314 ANG Bryony Thompson Gene: ang has been classified as Red List (Low Evidence).
Early-onset Parkinson disease v0.314 ANG Bryony Thompson gene: ANG was added
gene: ANG was added to Early-onset Parkinson disease. Sources: Literature
Mode of inheritance for gene: ANG was set to Unknown
Publications for gene: ANG were set to 33875291; 25386690
Phenotypes for gene: ANG were set to Parkinson disease MONDO:0005180
Review for gene: ANG was set to RED
Added comment: Multiple large studies not finding an association with PD
Sources: Literature
Early-onset Parkinson disease v0.313 FUS Bryony Thompson changed review comment from: A single family reported p.Gln290* segregating (incomplete penetrance) with essential tremor, also two missense variants reported in 2 probands which are too common in gnomAD and have been classified as LB in ClinVar. A reported ET risk variant Met392Ile in a Chinese population - set 1 odds ratio = 4.72 [95% confidence interval = 1.90-11.71], p = 0.0037). Validation set 2 (joint analysis odds ratio = 3.92 [95% confidence interval = 1.57-9.82], p = 8.6 × 10(-4). This variant has been classified as LB in ClinVar.
Sources: Literature; to: A single family reported p.Gln290* segregating (incomplete penetrance) with essential tremor, also two missense variants reported in 2 probands which are too common in gnomAD and have been classified as LB in ClinVar. One of these (Pro431Leu) was also reported in an Italian family. A reported ET risk variant Met392Ile in a Chinese population - set 1 odds ratio = 4.72 [95% confidence interval = 1.90-11.71], p = 0.0037). Validation set 2 (joint analysis odds ratio = 3.92 [95% confidence interval = 1.57-9.82], p = 8.6 × 10(-4). This variant has been classified as LB in ClinVar.
Sources: Literature
Early-onset Parkinson disease v0.313 FUS Bryony Thompson edited their review of gene: FUS: Changed publications: 22863194, 23834483, 23825177, 38626532
Early-onset Parkinson disease v0.311 MAPT Bryony Thompson Phenotypes for gene: MAPT were changed from to late-onset Parkinson disease MONDO:0008199
Early-onset Parkinson disease v0.310 MAPT Bryony Thompson Mode of inheritance for gene: MAPT was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.309 MAPT Bryony Thompson Mode of inheritance for gene: MAPT was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.304 LYST Bryony Thompson Phenotypes for gene: LYST were changed from to Chediak-Higashi syndrome MONDO:0008963
Early-onset Parkinson disease v0.303 LYST Bryony Thompson Mode of inheritance for gene: LYST was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Parkinson disease v0.300 KIF5A Bryony Thompson Phenotypes for gene: KIF5A were changed from to Spastic paraplegia 10, autosomal dominant MIM#604187
Early-onset Parkinson disease v0.298 KIF5A Bryony Thompson Mode of inheritance for gene: KIF5A was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.296 LRRK2 Zornitza Stark Mode of inheritance for gene: LRRK2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.295 PTRHD1 Zornitza Stark Phenotypes for gene: PTRHD1 were changed from early-onset parkinsonism; intellectual disability to Neurodevelopmental disorder with early-onset parkinsonism and behavioral abnormalities, MIM# 620747
Early-onset Parkinson disease v0.292 FTL Bryony Thompson Mode of inheritance for gene: FTL was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.289 FBXO7 Bryony Thompson Phenotypes for gene: FBXO7 were changed from to parkinsonian-pyramidal syndrome MONDO:0009830
Early-onset Parkinson disease v0.288 FBXO7 Bryony Thompson Mode of inheritance for gene: FBXO7 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Parkinson disease v0.287 DNAJC6 Bryony Thompson Phenotypes for gene: DNAJC6 were changed from to juvenile onset Parkinson disease 19A MONDO:0014231
Early-onset Parkinson disease v0.285 DNAJC6 Bryony Thompson Mode of inheritance for gene: DNAJC6 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Parkinson disease v0.284 DCTN1 Bryony Thompson Phenotypes for gene: DCTN1 were changed from Perry syndrome MONDO:0008201 to Perry syndrome MONDO:0008201
Early-onset Parkinson disease v0.283 DCTN1 Bryony Thompson Phenotypes for gene: DCTN1 were changed from to Perry syndrome MONDO:0008201
Early-onset Parkinson disease v0.281 DCTN1 Bryony Thompson Mode of inheritance for gene: DCTN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.281 DCTN1 Bryony Thompson Mode of inheritance for gene: DCTN1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.280 DCTN1 Bryony Thompson Mode of inheritance for gene: DCTN1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.279 CSF1R Bryony Thompson Phenotypes for gene: CSF1R were changed from to leukoencephalopathy, diffuse hereditary, with spheroids 1 MONDO:0800027
Early-onset Parkinson disease v0.277 CSF1R Bryony Thompson Mode of inheritance for gene: CSF1R was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.275 C19orf12 Bryony Thompson Phenotypes for gene: C19orf12 were changed from to neurodegeneration with brain iron accumulation 4 MONDO:0013674
Early-onset Parkinson disease v0.273 C19orf12 Bryony Thompson Mode of inheritance for gene: C19orf12 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.272 ATP1A3 Bryony Thompson Phenotypes for gene: ATP1A3 were changed from to ATP1A3-associated neurological disorder MONDO:0700002
Early-onset Parkinson disease v0.270 ATP1A3 Bryony Thompson Mode of inheritance for gene: ATP1A3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.268 ATP13A2 Bryony Thompson Phenotypes for gene: ATP13A2 were changed from to parkinsonism due to ATP13A2 deficiency MONDO:0017809
Early-onset Parkinson disease v0.266 ATP13A2 Bryony Thompson Mode of inheritance for gene: ATP13A2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Parkinson disease v0.264 SLC30A10 Claire Fryer-Smith reviewed gene: SLC30A10: Rating: GREEN; Mode of pathogenicity: None; Publications: 22341971, 22341972; Phenotypes: Hypermanganesemia with dystonia 1 (MIM# 613280); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early-onset Parkinson disease v0.264 SLC39A14 Zornitza Stark Phenotypes for gene: SLC39A14 were changed from to Hypermanganesemia with dystonia 2 (MIM# 617013)
Early-onset Parkinson disease v0.262 SLC39A14 Zornitza Stark Mode of inheritance for gene: SLC39A14 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Early-onset Parkinson disease v0.261 SLC39A14 Zornitza Stark Mode of inheritance for gene: SLC39A14 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Parkinson disease v0.260 SLC39A14 Claire Fryer-Smith reviewed gene: SLC39A14: Rating: GREEN; Mode of pathogenicity: None; Publications: 27231142, 32626807, 29685658, 30232769; Phenotypes: Hypermanganesemia with dystonia 2 (MIM# 617013); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early-onset Parkinson disease v0.260 PANK2 Zornitza Stark Phenotypes for gene: PANK2 were changed from pantothenate kinase-associated neurodegeneration MONDO:0009319 to pantothenate kinase-associated neurodegeneration MONDO:0009319
Early-onset Parkinson disease v0.259 PANK2 Zornitza Stark Phenotypes for gene: PANK2 were changed from pantothenate kinase-associated neurodegeneration MONDO:0009319 to pantothenate kinase-associated neurodegeneration MONDO:0009319
Early-onset Parkinson disease v0.258 PANK2 Zornitza Stark Phenotypes for gene: PANK2 were changed from to pantothenate kinase-associated neurodegeneration MONDO:0009319
Early-onset Parkinson disease v0.256 PANK2 Zornitza Stark Mode of inheritance for gene: PANK2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Parkinson disease v0.255 PLA2G6 Zornitza Stark Phenotypes for gene: PLA2G6 were changed from to autosomal recessive Parkinson disease 14 MONDO:0013060
Early-onset Parkinson disease v0.253 PLA2G6 Zornitza Stark Mode of inheritance for gene: PLA2G6 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Parkinson disease v0.252 POLG Zornitza Stark Phenotypes for gene: POLG were changed from to autosomal dominant progressive external ophthalmoplegia MONDO:0008003
Early-onset Parkinson disease v0.250 POLG Zornitza Stark Mode of inheritance for gene: POLG was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.249 PRKRA Zornitza Stark Phenotypes for gene: PRKRA were changed from to dystonia 16 MONDO:0012789
Early-onset Parkinson disease v0.247 PRKRA Zornitza Stark Mode of inheritance for gene: PRKRA was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Parkinson disease v0.246 PRNP Zornitza Stark Phenotypes for gene: PRNP were changed from to inherited Creutzfeldt-Jakob disease MONDO:0007403; Gerstmann-Straussler-Scheinker syndrome MONDO:0007656
Early-onset Parkinson disease v0.244 PRNP Zornitza Stark Mode of inheritance for gene: PRNP was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.243 PANK2 Kaitlyn Dianna Weldon edited their review of gene: PANK2: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early-onset Parkinson disease v0.243 FTL Kaitlyn Dianna Weldon edited their review of gene: FTL: Changed rating: GREEN
Early-onset Parkinson disease v0.242 PTPA Zornitza Stark Mode of inheritance for gene: PTPA was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early-onset Parkinson disease v0.241 PTPA Zornitza Stark Mode of inheritance for gene: PTPA was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early-onset Parkinson disease v0.241 PTPA Zornitza Stark Mode of inheritance for gene: PTPA was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early-onset Parkinson disease v0.237 Zornitza Stark HPO terms changed from to Abnormality of extrapyramidal motor function, HP:0002071
List of related panels changed from to Abnormality of extrapyramidal motor function; HP:0002071
Early-onset Parkinson disease v0.236 AFG3L2 Zornitza Stark Phenotypes for gene: AFG3L2 were changed from to Spinocerebellar ataxia 28, MIM# 610246; optic atrophy; spastic ataxia; L-dopa-responsive parkinsonism
Early-onset Parkinson disease v0.235 AFG3L2 Zornitza Stark Mode of inheritance for gene: AFG3L2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.231 PTPA Zornitza Stark gene: PTPA was added
gene: PTPA was added to Early-onset Parkinson disease. Sources: Literature
Mode of inheritance for gene: PTPA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTPA were set to 36073231
Phenotypes for gene: PTPA were set to Intellectual disability, MONDO: 36073231, PTPA-related; Parkisonism
Review for gene: PTPA was set to AMBER
Added comment: Biallelic PTPA pathogenic variants lead to a form of ID with later-onset parkinsonism based on 4 individuals from 2 families in the literature. Affected individuals were homozygous for missense variants demonstrated to result to reduced mRNA and protein levels as well as PP2A complex activation. Drosophila studies support an age-dependent locomotor dysfunction. Variants in other PP2A-complex-related genes also lead to NDDs. Summary provided below.

There is currently no associated phenotype in OMIM, G2P, PanelApp UK or SysID.

Consider inclusion in relevant panels (ID, Parkinsonism/movement disorders, etc) with amber rating pending further reports.

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Fevga, Tesson et al (2022 - PMID: 36073231) describe the features of 4 individuals, from 2 unrelated families, with biallelic pathogenic PTPA variants.

These presented with normal or delayed early milestones, learning disability and ID (mild to moderate) followed by progressive signs of parkinsonism (at the age of 11 yrs in 2 sibs, 15 yrs in another individual). Motor symptoms were responsive to levodopa and later to deep brain stimulation.

Linkage analysis in one consanguineous family followed by exome revealed homozygosity for a missense PTPA variant (NM_178001:c.893T>G/p.Met298Arg). Exome sequencing in affected subjects from the 2nd family revealed homozygosity for a further missense variant (c.512C>A/p.Ala171Asp). There were no other candidate variants for the phenotype following parental / segregation studies.

Role of the gene:
As the authors discuss, PTPA (or PPP2R4) is ubiquitously expressed in all tissues incl. brain and encodes a phosphotyrosyl phosphatase activator of the dimeric form of protein phosphatase-2A (PP2A). PP2A in turn, is the major Ser/Thr phosphatase in brain targeting a large number of proteins involved in diverse functions. Activation of PP2A is dependent on its methylation, which is negatively regulated by the PP2A-specific methylesterase (PME-1). By binding to PME-1, PTPA counteracts the negative influence of the former on PP2A. Pathogenic variants in genes encoding subunits/regulators of the PP2A complex (e.g. PPP2R1A or PPP2CA) are associated with neurodevelopmental disorders.

Variant studies:
Upon overexpression of wt and both variants in a HEK-293 cell line the authors demonstrated that both variants resulted in significantly reduced mRNA and protein levels (which for Ala171Asp were attributed to increased proteasomal degradation). Both variants were shown to result in impaired PP2A complex activation compared to wt.

Drosophila / animal models:
Pan-neuronal RNAi-mediated knockdown of ptpa in Drosophila resulted in an age-dependent locomotor dysfunction, reversible with L-DOPA treatment.
Previous studies in mice suggest cognitive/electrophysiological impairments upon downregulation of PP2A activity in transgenic mice.
Sources: Literature
Early-onset Parkinson disease v0.229 WASL Zornitza Stark Phenotypes for gene: WASL were changed from Early onset parkinsonism to Parkinson's disease, MONDO:0005180, WASL-related
Early-onset Parkinson disease v0.227 KMT2B Zornitza Stark Phenotypes for gene: KMT2B were changed from DYT28; Childhood‐onset and progressive dystonia; Dysarthria; Dysphagia; Developmental delay; Dysmorphic features; Parkinsonism; OMIM 617284 to Dystonia 28, childhood-onset , MIM#617284
Early-onset Parkinson disease v0.226 KMT2B Zornitza Stark Mode of inheritance for gene: KMT2B was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.224 GBA Zornitza Stark Phenotypes for gene: GBA were changed from Gaucher Disease Type 1; Early onset parkinsonism; Bone lesions; Hepatosplenomegaly; Hematologic disorders; OMIM 230800 to Parkinson's disease, MONDO:0005180, GBA-related
Early-onset Parkinson disease v0.222 GBA Zornitza Stark Mode of inheritance for gene: GBA was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.220 FRRS1L Zornitza Stark Phenotypes for gene: FRRS1L were changed from Developmental and epileptic dyskinetic encephalopathy; Seizures; Chorea; Parkinsonism; Developmental delay; OMIM 616981 to Developmental and epileptic encephalopathy 37, MIM# 616981; Seizures; Chorea; Parkinsonism; Developmental delay
Early-onset Parkinson disease v0.218 ALPL Zornitza Stark Phenotypes for gene: ALPL were changed from Hypophosphatasia; Osteomalacia; Parkinsonism; OMIM 146300 to Hypophosphatasia, adult, MIM# 146300; Osteomalacia; Parkinsonism
Early-onset Parkinson disease v0.215 KIAA1161 Zornitza Stark Phenotypes for gene: KIAA1161 were changed from Primary familial brain calcification; Atypical parkinsonism; Supranuclear gaze palsy; OMIM 618317 to Basal ganglia calcification, idiopathic, 7, autosomal recessive, OMIM #618317; Primary familial brain calcification; Atypical parkinsonism; Supranuclear gaze palsy
Early-onset Parkinson disease v0.212 KIAA1161 Zornitza Stark reviewed gene: KIAA1161: Rating: GREEN; Mode of pathogenicity: None; Publications: 30656188, 30649222, 30460687, 29910000, 31951047; Phenotypes: Basal ganglia calcification, idiopathic, 7, autosomal recessive, OMIM #618317; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early-onset Parkinson disease v0.212 NHLRC1 Zornitza Stark Phenotypes for gene: NHLRC1 were changed from Lafora disease; Progressive Myoclonic Epilepsy; Parkinsonism; OMIM 254780 to Epilepsy, progressive myoclonic 2B (Lafora), MIM# 254780; Lafora disease; Progressive Myoclonic Epilepsy; Parkinsonism
Early-onset Parkinson disease v0.210 C9orf3 Zornitza Stark Phenotypes for gene: C9orf3 were changed from Dystonia-31; Childhood/Adolescence onset generalised dystonia; Dystonia parkinsonism; Zech-Boesch Syndrome; OMIM 619565 to Dystonia 31, MIM# 619565; Childhood/Adolescence onset generalised dystonia; Dystonia parkinsonism; Zech-Boesch Syndrome
Early-onset Parkinson disease v0.207 TPP1 Zornitza Stark Phenotypes for gene: TPP1 were changed from Late Infantile NCL; Parkinsonism; OMIM 204500 to Ceroid lipofuscinosis, neuronal, 2, MIM# 204500; Parkinsonism
Early-onset Parkinson disease v0.205 CYP27A1 Zornitza Stark Phenotypes for gene: CYP27A1 were changed from Cerebrotendinous xanthomatosis, infantile-onset diarrhoea, juvenile-onset cataract, young adult-onset tendon xanthomas; Epilepsy; Parkinsonism; Ataxia; Peripheral neuropathy; OMIM 213700 to Cerebrotendinous xanthomatosis, MIM# 213700; Cerebrotendinous xanthomatosis, infantile-onset diarrhoea, juvenile-onset cataract, young adult-onset tendon xanthomas; Epilepsy; Parkinsonism; Ataxia; Peripheral neuropathy
Early-onset Parkinson disease v0.203 DDC Zornitza Stark Phenotypes for gene: DDC were changed from Aromatic L-amino acid decarboxylase deficiency (DYT-DDC); Infantile-onset parkinsonism & dystonia; Bulbar dysfunction; Oculogyric crisis; Autonomic dysfunction; Intellectual disability; OMIM 608603 to Aromatic L-amino acid decarboxylase deficiency, MIM# 608643; Infantile-onset parkinsonism & dystonia; Bulbar dysfunction; Oculogyric crisis; Autonomic dysfunction; Intellectual disability
Early-onset Parkinson disease v0.201 DHDDS Zornitza Stark Phenotypes for gene: DHDDS were changed from Myoclonic Epilepsy; Parkinsonism; Ataxia; Intellectual disability; OMIM 617836 to Developmental delay and seizures with or without movement abnormalities, MIM# 617836; Myoclonic Epilepsy; Parkinsonism; Ataxia; Intellectual disability
Early-onset Parkinson disease v0.198 EIF2AK2 Zornitza Stark Phenotypes for gene: EIF2AK2 were changed from Neurodevelopmental Syndrome; Developmental delays; Ataxia; Parkinsonism; White matter alterations; OMIM 618877 to Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome, MIM# 618877; Neurodevelopmental Syndrome; Developmental delays; Ataxia; Parkinsonism; White matter alterations
Early-onset Parkinson disease v0.197 EIF2AK2 Zornitza Stark Mode of inheritance for gene: EIF2AK2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.195 EPM2A Zornitza Stark Phenotypes for gene: EPM2A were changed from Lafora disease; Progressive Myoclonic Epilepsy; Parkinsonism; OMIM 254780 to Epilepsy, progressive myoclonic 2A (Lafora), MIM# 254780; Progressive Myoclonic Epilepsy; Parkinsonism
Early-onset Parkinson disease v0.192 FOXG1 Zornitza Stark Phenotypes for gene: FOXG1 were changed from Developmental and Epileptic Encephalopathy; Dystonia,; Athetosis; Parkinsonism; Stereotypies; OMIM 613454 to Rett syndrome, congenital variant, MIM# 613454; Developmental and Epileptic Encephalopathy; Dystonia,; Athetosis; Parkinsonism; Stereotypies
Early-onset Parkinson disease v0.191 GLB1 Zornitza Stark changed review comment from: Reported in Type 3.; to: Parkinsonism reported in Type 3.
Early-onset Parkinson disease v0.191 GLB1 Zornitza Stark Phenotypes for gene: GLB1 were changed from GM1 Gangliosidosis; Parkinsonism; OMIM 230650 to GM1-gangliosidosis, type III , MIM#230650; Parkinsonism
Early-onset Parkinson disease v0.189 GLB1 Zornitza Stark reviewed gene: GLB1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: GM1-gangliosidosis, type III , MIM#230650; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early-onset Parkinson disease v0.189 HEXA Zornitza Stark edited their review of gene: HEXA: Changed rating: RED; Changed phenotypes: Tay-Sachs disease, MIM# 272800; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early-onset Parkinson disease v0.187 NPC2 Zornitza Stark Phenotypes for gene: NPC2 were changed from Niemann Pick C2; Parkinsonism; OMIM 607625 to Niemann Pick C2, OMIM 607625; Parkinsonism
Early-onset Parkinson disease v0.185 NPC1 Zornitza Stark Phenotypes for gene: NPC1 were changed from Niemann Pick C1; Parkinsonism; OMIM 257220 to Niemann-Pick disease, MIM# 257220; Parkinsonism
Early-onset Parkinson disease v0.183 NPC1 Zornitza Stark Mode of inheritance for gene: NPC1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early-onset Parkinson disease v0.181 NUS1 Zornitza Stark Phenotypes for gene: NUS1 were changed from Mental retardation 55 with seizures (MRD55); Parkinsonism; Developmental delay; Intellectual disability; Ataxia; Myoclonus; OMIM 617831 to Intellectual developmental disorder, autosomal dominant 55, with seizures, MIM# 617831; Parkinsonism; Developmental delay; Intellectual disability; Ataxia; Myoclonus
Early-onset Parkinson disease v0.180 NUS1 Zornitza Stark Mode of inheritance for gene: NUS1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.178 PGK1 Zornitza Stark Phenotypes for gene: PGK1 were changed from Haemolytic anaemia; Rhabdomyolysis; Myopathy; Juvenile Parkinsonism; OMIM 300653 to Phosphoglycerate kinase 1 deficiency, MIM# 300653; Haemolytic anaemia; Rhabdomyolysis; Myopathy; Juvenile Parkinsonism; OMIM 300653
Early-onset Parkinson disease v0.176 POLR3A Zornitza Stark Phenotypes for gene: POLR3A were changed from POLR3A Leukoencephalopathy; Parkinsonism; Ocular and dental abnormality; Hypogonadism, OMIM 607694 to Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, MIM# 607694; POLR3A Leukoencephalopathy; Parkinsonism; Ocular and dental abnormality; Hypogonadism
Early-onset Parkinson disease v0.174 PRKCG Zornitza Stark Phenotypes for gene: PRKCG were changed from Spinocerebellar ataxia 14; Myoclonus; Parkinsonism; OMIM 605361 to Spinocerebellar ataxia 14, MIM# 605361; Myoclonus; Parkinsonism
Early-onset Parkinson disease v0.173 PRKCG Zornitza Stark Mode of inheritance for gene: PRKCG was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.171 QDPR Zornitza Stark Phenotypes for gene: QDPR were changed from Dehydropteridin reductase deficiency, Infantile-onset dystonia; Parkinsonism; Epilepsy; Autonomic dysfunction; Hyperphenylalaninemia; OMIM 261360 to Hyperphenylalaninemia, BH4-deficient, C, MIM#261630; Dehydropteridin reductase deficiency, Infantile-onset dystonia; Parkinsonism; Epilepsy; Autonomic dysfunction; Hyperphenylalaninemia
Early-onset Parkinson disease v0.169 SCN1A Zornitza Stark Phenotypes for gene: SCN1A were changed from Dravet syndrome; Epilepsy, Paekinsonism; OMIM 607208 to Dravet syndrome, MIM# 607208; Epilepsy, Paekinsonism
Early-onset Parkinson disease v0.168 SCN1A Zornitza Stark Mode of inheritance for gene: SCN1A was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.166 SERAC1 Zornitza Stark Phenotypes for gene: SERAC1 were changed from MEGDEL Syndrome; Parkinsonism to 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome, MIM# 614739; Parkinsonism
Early-onset Parkinson disease v0.164 SLC19A3 Zornitza Stark Phenotypes for gene: SLC19A3 were changed from Biotin-Thiamine Responsive Basal Ganglia disease; Childhood onset Dystonia and Parkinsonism; OMIM 607483 to Thiamine metabolism dysfunction syndrome 2 (biotin- or thiamine-responsive encephalopathy type 2), MIM# 607483; Childhood onset Dystonia and Parkinsonism
Early-onset Parkinson disease v0.162 SLC18A2 Zornitza Stark Phenotypes for gene: SLC18A2 were changed from Brain dopamine-serotonin transport disease, Childhood-onset parkinsonism, OMIM 618049 to Parkinsonism-dystonia, infantile, 2 , MIM# 618049; Brain dopamine-serotonin transport disease, Childhood-onset parkinsonism
Early-onset Parkinson disease v0.158 SOX6 Zornitza Stark Phenotypes for gene: SOX6 were changed from Tolchin-Le Caignec syndrome; Developmental delay; ID; ASD; ADHD; Parkinsonism; Syringomyelia, OMIM 618971 to Tolchin-Le Caignec syndrome, MIM# 618971; Developmental delay; ID; ASD; ADHD; Parkinsonism; Syringomyelia
Early-onset Parkinson disease v0.157 SOX6 Zornitza Stark Mode of inheritance for gene: SOX6 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.155 SPG7 Zornitza Stark Phenotypes for gene: SPG7 were changed from Hereditary Spastic Paraplegia 7; Ataxia; Progressive external opthalmoplegia; Parkinsonism; OMIM 607259 to Spastic paraplegia 7, autosomal recessive, MIM# 607259; Ataxia; Progressive external opthalmoplegia; Parkinsonism
Early-onset Parkinson disease v0.153 STUB1 Zornitza Stark Phenotypes for gene: STUB1 were changed from Spinocerebellar Ataxia 48; Parkinsonism, OMIM 618093 to Spinocerebellar Ataxia 48, OMIM 618093; Parkinsonism
Early-onset Parkinson disease v0.152 STUB1 Zornitza Stark Mode of inheritance for gene: STUB1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.151 STUB1 Zornitza Stark Mode of inheritance for gene: STUB1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.150 STXBP1 Zornitza Stark Phenotypes for gene: STXBP1 were changed from Developmental and epileptic encephalopathy 4; Juvenile onset Parkinsonism; OMIM 612164 to Developmental and epileptic encephalopathy 4, MIM# 612164; Juvenile onset Parkinsonism
Early-onset Parkinson disease v0.148 STXBP1 Zornitza Stark Mode of inheritance for gene: STXBP1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.146 TBC1D24 Zornitza Stark Phenotypes for gene: TBC1D24 were changed from Developmental and epileptic encephalopathy 16; Intellectual disability; Parkinsonism; Seizures; Psychosis; OMIM 615338 to Developmental and epileptic encephalopathy 16, MIM# 615338; Intellectual disability; Parkinsonism; Seizures; Psychosis
Early-onset Parkinson disease v0.144 UBTF Zornitza Stark Phenotypes for gene: UBTF were changed from Neurodegeneration, childhood-onset; Parkinsonism; Dystonia; Chorea; Brain atrophy to Neurodegeneration, childhood-onset, with brain atrophy, MIM# 617672; Parkinsonism; Dystonia; Chorea; Brain atrophy
Early-onset Parkinson disease v0.143 UBTF Zornitza Stark Mode of inheritance for gene: UBTF was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.141 VAC14 Zornitza Stark Phenotypes for gene: VAC14 were changed from Childhood onset Striatonigral degeneration; Dystonia; Parkinsonism; OMIM 617054 to Striatonigral degeneration, childhood-onset, MIM# 617054; Dystonia; Parkinsonism
Early-onset Parkinson disease v0.139 WARS2 Zornitza Stark Phenotypes for gene: WARS2 were changed from Parkinsonism-dystonia 3, childhood-onset, MIM# 619738 to Parkinsonism-dystonia 3, childhood-onset, MIM# 619738
Early-onset Parkinson disease v0.139 WARS2 Zornitza Stark Phenotypes for gene: WARS2 were changed from Childhood onset parkinsonism dystonia-3; Myoclonus ataxia; OMIM 619738 to Parkinsonism-dystonia 3, childhood-onset, MIM# 619738
Early-onset Parkinson disease v0.136 ZFYVE26 Zornitza Stark Phenotypes for gene: ZFYVE26 were changed from Spastic paraplegia and retinal degeneration; Kjellin syndrome; Parkinsonism; OMIM 270700 to Spastic paraplegia 15, autosomal recessive, MIM# 270700; Spastic paraplegia and retinal degeneration; Kjellin syndrome; Parkinsonism
Early-onset Parkinson disease v0.134 GLB1 SHEKEEB MOHAMMAD gene: GLB1 was added
gene: GLB1 was added to Early-onset Parkinson disease. Sources: Literature
Mode of inheritance for gene: GLB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GLB1 were set to PMID: 34514040
Phenotypes for gene: GLB1 were set to GM1 Gangliosidosis; Parkinsonism; OMIM 230650
Review for gene: GLB1 was set to GREEN
Added comment: Sources: Literature
Early-onset Parkinson disease v0.134 HEXA SHEKEEB MOHAMMAD gene: HEXA was added
gene: HEXA was added to Early-onset Parkinson disease. Sources: Literature
Mode of inheritance for gene: HEXA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HEXA were set to PMID: 33069254
Phenotypes for gene: HEXA were set to GM2 Gangliosidosis; Tay-Sachs disease; Parkinsonism; OMIM 272800
Review for gene: HEXA was set to GREEN
Added comment: Sources: Literature
Early-onset Parkinson disease v0.134 NPC1 SHEKEEB MOHAMMAD edited their review of gene: NPC1: Changed publications: PMID: 24035292, 30369906
Early-onset Parkinson disease v0.134 SLC19A3 SHEKEEB MOHAMMAD gene: SLC19A3 was added
gene: SLC19A3 was added to Early-onset Parkinson disease. Sources: Literature
Mode of inheritance for gene: SLC19A3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC19A3 were set to PMID: 24260777
Phenotypes for gene: SLC19A3 were set to Biotin-Thiamine Responsive Basal Ganglia disease; Childhood onset Dystonia and Parkinsonism; OMIM 607483
Review for gene: SLC19A3 was set to GREEN
Added comment: Sources: Literature
Early-onset Parkinson disease v0.134 NR4A2 Zornitza Stark Phenotypes for gene: NR4A2 were changed from Intellectual Disability; Dystonia and Early-onset Parkinson to Intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonism, MIM# 619911
Early-onset Parkinson disease v0.129 FMR1 Bryony Thompson Phenotypes for gene: FMR1 were changed from Fragile X tremor/ataxia syndrome MIM#300623; Fragile X syndrome MIM#300624 to Fragile X tremor/ataxia syndrome MIM#300623
Early-onset Parkinson disease v0.127 FMR1 Bryony Thompson changed review comment from: Parkinsonism can be a relatively common feature of the condition. The major cause of the condition is 5'UTR repeat expansion, but at least 6 pathogenic intragenic SNV or small indels have been reported in affected males.; to: Parkinsonism can be a relatively common feature of FXTAS, which is caused by 5'UTR repeat expansion.
Early-onset Parkinson disease v0.127 FMR1 Bryony Thompson edited their review of gene: FMR1: Changed publications: 27340021, 28176767, 20301558; Changed phenotypes: Fragile X tremor/ataxia syndrome MIM#300623
Early-onset Parkinson disease v0.126 SYNJ1 Zornitza Stark Phenotypes for gene: SYNJ1 were changed from to Parkinson disease 20, early-onset, MIM# 615530
Early-onset Parkinson disease v0.124 SYNJ1 Zornitza Stark Mode of inheritance for gene: SYNJ1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Parkinson disease v0.123 VPS35 Zornitza Stark Phenotypes for gene: VPS35 were changed from to Parkinson disease 17, MIM# 614203
Early-onset Parkinson disease v0.121 VPS35 Zornitza Stark Mode of inheritance for gene: VPS35 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.119 NIID Bryony Thompson STR: NIID was added
STR: NIID was added to Early-onset Parkinson disease. Sources: Literature
Mode of inheritance for STR: NIID was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: NIID were set to 31178126; 31332381; 31819945; 33887199; 33943039; 32250060; 31332380; 32852534; 32989102; 34333668
Phenotypes for STR: NIID were set to Neuronal intranuclear inclusion disease MIM#603472; Oculopharyngodistal myopathy 3 MIM#619473; Tremor, hereditary essential, 6 MIM#618866
Review for STR: NIID was set to GREEN
STR: NIID was marked as clinically relevant
Added comment: NM_001364012.2:c.-164GGC[X]
Expanded repeat in NOTCH2NLC sequence is (GGC)9(GGA)2(GGC)2.
Large number of families and sporadic cases reported with expansions, with a range of neurodegenerative phenotypes, including: dementia, Parkinsonism/tremor, peripheral neuropathy, leukoencephalopathy, myopathy, motor neurone disease.
Normal repeat range: 4-40, 1 control had 61 repeats and may have been a presymptomatic carrier.
Intermediate range: 41-60 identified in Parkinson's disease
Pathogenic repeat range: >=60-520
Mechanism of disease is translation of repeat expansion into a toxic polyglycine protein, identified in both mouse models and tissue samples from affected individuals.
Sources: Literature
Early-onset Parkinson disease v0.115 XDP Bryony Thompson STR: XDP was added
STR: XDP was added to Early-onset Parkinson disease. Sources: Expert list
founder tags were added to STR: XDP.
Mode of inheritance for STR: XDP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: XDP were set to 17273961; 29229810
Phenotypes for STR: XDP were set to Dystonia-Parkinsonism, X-linked MIM#314250
Review for STR: XDP was set to GREEN
STR: XDP was marked as clinically relevant
Added comment: Founder Filipino variant. Associated with an antisense insertion of a SINE-VNTR-Alu (SVA)-type retrotransposon within an intron. The number of repeats in these cases ranged from 35 to 52 and showed a highly significant inverse correlation with age at disease onset. The mechanism of disease is unknown, possibly this intronic retroelement may induce transcriptional interference in TAF1 expression.
Sources: Expert list
Early-onset Parkinson disease v0.111 PSAP Zornitza Stark Phenotypes for gene: PSAP were changed from Parkinson Disease, AD to Parkinson disease 24, autosomal dominant, susceptibility to, MIM# 619491
Early-onset Parkinson disease v0.110 FMR1 Bryony Thompson Phenotypes for gene: FMR1 were changed from to Fragile X tremor/ataxia syndrome MIM#300623; Fragile X syndrome MIM#300624
Early-onset Parkinson disease v0.108 FMR1 Bryony Thompson Mode of inheritance for gene: FMR1 was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early-onset Parkinson disease v0.106 NIID Bryony Thompson STR: NIID was added
STR: NIID was added to Early-onset Parkinson disease. Sources: Literature
Mode of inheritance for STR: NIID was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: NIID were set to 31178126; 31332381; 31819945; 33887199; 33943039; 32250060; 31332380; 32852534; 32989102
Phenotypes for STR: NIID were set to Neuronal intranuclear inclusion disease MIM#603472; Tremor, hereditary essential, 6 MIM#618866
Review for STR: NIID was set to GREEN
STR: NIID was marked as clinically relevant
Added comment: NM_001364012.2:c.-164GGC[(66_517)] Large number of families and sporadic cases reported with expansions, with a range of neurodegenerative phenotypes, including: dementia, Parkinsonism/tremor, peripheral neuropathy, leukoencephalopathy, myopathy, motor neurone disease. Normal repeat range: 7-60 Pathogenic repeat range: >=61-500 Mechanism of disease is translation of repeat expansion into a toxic polyglycine protein, identified in both mouse models and tissue samples from affected individuals.
Sources: Literature
Early-onset Parkinson disease v0.105 PINK1 Zornitza Stark Phenotypes for gene: PINK1 were changed from to Parkinson disease 6, early onset MIM#605909
Early-onset Parkinson disease v0.103 PINK1 Zornitza Stark Mode of inheritance for gene: PINK1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Parkinson disease v0.102 UQCRC1 Zornitza Stark Phenotypes for gene: UQCRC1 were changed from Parkinson's disease to Parkinsonism with polyneuropathy, MIM# 619279
Early-onset Parkinson disease v0.101 UQCRC1 Zornitza Stark edited their review of gene: UQCRC1: Changed phenotypes: Parkinsonism with polyneuropathy, MIM# 619279
Early-onset Parkinson disease v0.101 PSAP Seb Lunke Phenotypes for gene: PSAP were changed from parkinson's disease to Parkinson Disease, AD
Early-onset Parkinson disease v0.98 PSAP Ain Roesley changed review comment from: 6 affecteds from 3 families. Age of onset ranges from 33-60.
Functional studies: Autophagic vacuole accumulation in skin fibroblasts , a-Synuclein aggregation and PSAP retention in the ER and abnormal intracellular accumulation in iPSC-dopaminergic neurons. Mouse model for one of 1 of the variants had motor deficits and dopaminergic neurodegeneration
Sources: Literature; to: - 6 affecteds from 3 families. Age of onset ranges from 33-60.
- 2x missense and 1 inframe del
- Functional studies: Autophagic vacuole accumulation in skin fibroblasts , a-Synuclein aggregation and PSAP retention in the ER and abnormal intracellular accumulation in iPSC-dopaminergic neurons. Mouse model for one of 1 of the variants had motor deficits and dopaminergic neurodegeneration
Sources: Literature
Early-onset Parkinson disease v0.98 PSAP Ain Roesley gene: PSAP was added
gene: PSAP was added to Early-onset Parkinson disease. Sources: Literature
Mode of inheritance for gene: PSAP was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PSAP were set to 32201884
Phenotypes for gene: PSAP were set to parkinson's disease
Penetrance for gene: PSAP were set to unknown
Review for gene: PSAP was set to GREEN
Added comment: 6 affecteds from 3 families. Age of onset ranges from 33-60.
Functional studies: Autophagic vacuole accumulation in skin fibroblasts , a-Synuclein aggregation and PSAP retention in the ER and abnormal intracellular accumulation in iPSC-dopaminergic neurons. Mouse model for one of 1 of the variants had motor deficits and dopaminergic neurodegeneration
Sources: Literature
Early-onset Parkinson disease v0.92 SNCA Zornitza Stark Phenotypes for gene: SNCA were changed from to Dementia, Lewy body (MIM#127750); Parkinson disease 1 (MIM#168601); Parkinson disease 4 (MIM#605543)
Early-onset Parkinson disease v0.90 SNCA Zornitza Stark Mode of inheritance for gene: SNCA was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.84 XPR1 Zornitza Stark Phenotypes for gene: XPR1 were changed from to Basal ganglia calcification, idiopathic, 6, MIM# 616413
Early-onset Parkinson disease v0.82 XPR1 Zornitza Stark Mode of inheritance for gene: XPR1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.81 XPR1 Zornitza Stark reviewed gene: XPR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25938945; Phenotypes: Basal ganglia calcification, idiopathic, 6, MIM# 616413; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.80 TWNK Zornitza Stark Phenotypes for gene: TWNK were changed from to Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 MIM#609286
Early-onset Parkinson disease v0.79 TAF1 Zornitza Stark Phenotypes for gene: TAF1 were changed from to Dystonia-Parkinsonism, X-linked, MIM# 314250
Early-onset Parkinson disease v0.77 TAF1 Zornitza Stark Mode of inheritance for gene: TAF1 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early-onset Parkinson disease v0.75 PDGFRB Zornitza Stark Phenotypes for gene: PDGFRB were changed from to Basal ganglia calcification, idiopathic, 4, MIM# 615007
Early-onset Parkinson disease v0.73 PDGFRB Zornitza Stark Mode of inheritance for gene: PDGFRB was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.72 PDGFRB Zornitza Stark reviewed gene: PDGFRB: Rating: GREEN; Mode of pathogenicity: None; Publications: 23255827, 30979360; Phenotypes: Basal ganglia calcification, idiopathic, 4 615007; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.72 PDGFB Zornitza Stark Phenotypes for gene: PDGFB were changed from to Basal ganglia calcification, idiopathic, 5, MIM# 615483
Early-onset Parkinson disease v0.70 PDGFB Zornitza Stark Mode of inheritance for gene: PDGFB was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.69 PDGFB Zornitza Stark reviewed gene: PDGFB: Rating: GREEN; Mode of pathogenicity: None; Publications: 23913003; Phenotypes: Basal ganglia calcification, idiopathic, 5, MIM# 615483; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.69 MECP2 Zornitza Stark Phenotypes for gene: MECP2 were changed from to MECP2-related disorders; Rett syndrome, MIM# 312750; Mental retardation, X-linked, syndromic 13, MIM# 300055
Early-onset Parkinson disease v0.67 MECP2 Zornitza Stark Mode of inheritance for gene: MECP2 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early-onset Parkinson disease v0.66 GRN Zornitza Stark Phenotypes for gene: GRN were changed from to Frontotemporal lobar degeneration with ubiquitin-positive inclusions, MIM# 607485
Early-onset Parkinson disease v0.64 GRN Zornitza Stark Mode of inheritance for gene: GRN was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.63 GCH1 Zornitza Stark Phenotypes for gene: GCH1 were changed from to Dystonia, DOPA-responsive, with or without hyperphenylalaninemia, MIM# 128230
Early-onset Parkinson disease v0.61 GCH1 Zornitza Stark Mode of inheritance for gene: GCH1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.60 DNAJC5 Zornitza Stark Phenotypes for gene: DNAJC5 were changed from to Ceroid lipofuscinosis, neuronal, 4, Parry type, MIM# 162350
Early-onset Parkinson disease v0.58 DNAJC5 Zornitza Stark Mode of inheritance for gene: DNAJC5 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.57 SLC20A2 Zornitza Stark Phenotypes for gene: SLC20A2 were changed from to Basal ganglia calcification, idiopathic, 1, MIM# 213600
Early-onset Parkinson disease v0.55 SLC20A2 Zornitza Stark Mode of inheritance for gene: SLC20A2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.54 SLC20A2 Zornitza Stark reviewed gene: SLC20A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22327515, 23334463; Phenotypes: Basal ganglia calcification, idiopathic, 1, MIM# 213600; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.54 COASY Zornitza Stark Phenotypes for gene: COASY were changed from to Neurodegeneration with brain iron accumulation 6, MIM# 615643
Early-onset Parkinson disease v0.52 COASY Zornitza Stark Mode of inheritance for gene: COASY was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Parkinson disease v0.50 CLN3 Zornitza Stark Phenotypes for gene: CLN3 were changed from to Ceroid lipofuscinosis, neuronal, 3 MIM#204200
Early-onset Parkinson disease v0.48 CLN3 Zornitza Stark Mode of inheritance for gene: CLN3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Parkinson disease v0.47 C9orf72 Zornitza Stark Phenotypes for gene: C9orf72 were changed from to Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 MIM#105550
Early-onset Parkinson disease v0.45 C9orf72 Zornitza Stark Mode of inheritance for gene: C9orf72 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.44 APP Zornitza Stark Phenotypes for gene: APP were changed from to Alzheimer disease 1, familial, MIM# 104300
Early-onset Parkinson disease v0.43 APP Zornitza Stark Mode of inheritance for gene: APP was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.36 SLC6A3 Zornitza Stark Phenotypes for gene: SLC6A3 were changed from Parkinsonism-dystonia, infantile, 1, MIM# 613135 to Parkinsonism-dystonia, infantile, 1, MIM# 613135
Early-onset Parkinson disease v0.36 SLC6A3 Zornitza Stark Phenotypes for gene: SLC6A3 were changed from to Parkinsonism-dystonia, infantile, 1, MIM# 613135
Early-onset Parkinson disease v0.34 SLC6A3 Zornitza Stark Mode of inheritance for gene: SLC6A3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Parkinson disease v0.31 PSEN2 Bryony Thompson changed review comment from: Parkinson disease and parkinsonism is not a prominent feature of Alzheimer disease caused by PSEN2. A couple of isolated cases with parkinsonism as a feature of the condition and a single family have been reported with established pathogenic variants and a VUS (PMID: 22118943, 26422362, 18427071). VUS or now likely benign/benign missense variants have been identified in a Parkinson Disease cases used in case-control studies (PMID: 29692703, 26522186).
Sources: Other; to: Parkinson disease and parkinsonism is not a prominent feature of Alzheimer disease caused by PSEN2. A couple of isolated cases with VUS and parkinsonism as a feature of the condition and a single family with multiple members with parkinsonism with pathogenic missense variant have been reported (PMID: 22118943, 26422362, 18427071). VUS or now likely benign/benign missense variants have been identified in Parkinson Disease cases used in case-control studies (PMID: 29692703, 26522186).
Sources: Other
Early-onset Parkinson disease v0.31 PSEN2 Bryony Thompson changed review comment from: Parkinson disease and parkinsonism is not a prominent feature of Alzheimer disease caused by PSEN2. A couple of isolated cases with parkinsonism as a feature of the condition and a single family have been reported with established pathogenic or probable pathogenic variants (PMID: 22118943, 26422362, 18427071). VUS or now likely benign/benign missense variants have been identified in a Parkinson Disease cases used in case-control studies (PMID: 29692703, 26522186).
Sources: Other; to: Parkinson disease and parkinsonism is not a prominent feature of Alzheimer disease caused by PSEN2. A couple of isolated cases with parkinsonism as a feature of the condition and a single family have been reported with established pathogenic variants and a VUS (PMID: 22118943, 26422362, 18427071). VUS or now likely benign/benign missense variants have been identified in a Parkinson Disease cases used in case-control studies (PMID: 29692703, 26522186).
Sources: Other
Early-onset Parkinson disease v0.28 PODXL Bryony Thompson gene: PODXL was added
gene: PODXL was added to Early-onset Parkinson disease. Sources: Literature
Mode of inheritance for gene: PODXL was set to Unknown
Publications for gene: PODXL were set to 26864383; 20706633
Phenotypes for gene: PODXL were set to juvenile-onset Parkinson disease
Review for gene: PODXL was set to AMBER
Added comment: Single consanguineous Indian family reported with a homozygous loss of function variant. A Podxl null mouse model has aberrant neurite length and number of branching points, and also evidence of impaired synaptogenesis. Subsequent screening in 280 Parkinson disease patients with various ages of onset identified 3 heterozygous missense variants (P429T, S373N, and R294Q; all numbering according to isoform 2), absent in gnomAD. Transfection of the missense variants into PC12 cells resulted in variable aberrant neurite length and/or branching, suggesting a functional effect. However, there is more evidence supporting the association of monoallelic and biallelic variants with FSGS (see Proteinuria panel). There was no renal symptoms present in the reported family, which had renal function tests.
Sources: Literature
Early-onset Parkinson disease v0.27 Bryony Thompson Panel name changed from Early onset Parkinson disease to Early-onset Parkinson disease
Panel types changed to Melbourne Genomics; Victorian Clinical Genetics Services; Royal Melbourne Hospital
Early-onset Parkinson disease v0.24 TWNK Bryony Thompson Mode of inheritance for gene: TWNK was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.23 PTS Bryony Thompson Mode of inheritance for gene: PTS was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Parkinson disease v0.18 C9orf72 Bryony Thompson changed review comment from: Comment on list classification: A repeat expansion is the cause of disease for this gene, which is currently not detectable by NGS.; to: Parkinsonism is a common feature of the condition. A repeat expansion is the cause of disease for this gene.
Early-onset Parkinson disease v0.18 C9orf72 Bryony Thompson changed review comment from: Comment on list classification: A repeat expansion is the cause of disease for this gene, which is currently not detectable by NGS.; to: Comment on list classification: A repeat expansion is the cause of disease for this gene, which is currently not detectable by NGS.
Early-onset Parkinson disease v0.18 C9orf72 Bryony Thompson edited their review of gene: C9orf72: Changed rating: GREEN; Changed publications: 31779815; Changed phenotypes: Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 MIM#105550; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v0.16 DNAJC13 Bryony Thompson edited their review of gene: DNAJC13: Changed phenotypes: Parkinson disease 21, MIM#616361
Early-onset Parkinson disease v0.12 CHCHD2 Bryony Thompson edited their review of gene: CHCHD2: Changed publications: 32068847, 25662902, 31600778, 26705026
Early-onset Parkinson disease v0.7 Zornitza Stark Panel name changed from Early onset Parkinson disease_MelbourneGenomics_VCGS to Early onset Parkinson disease
Panel types changed to Victorian Clinical Genetics Services; Melbourne Genomics
Early-onset Parkinson disease v0.4 CP Zornitza Stark Phenotypes for gene: CP were changed from to Aceruloplasminaemia, MIM#604290
Early-onset Parkinson disease v0.3 CP Zornitza Stark Mode of inheritance for gene: CP was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Parkinson disease v0.1 PDE8B Zornitza Stark gene: PDE8B was added
gene: PDE8B was added to Early onset Parkinson disease_MelbourneGenomics_VCGS. Sources: Expert Review
Mode of inheritance for gene: PDE8B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PDE8B were set to 20085714; 26769607; 26475694
Phenotypes for gene: PDE8B were set to Striatal degeneration, autosomal dominant, MIM#609161
Review for gene: PDE8B was set to GREEN
Added comment: Movement disorder due to basal ganglia abnormalities, at least three families reported with heterozygous variants in this gene.
Sources: Expert Review