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| 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. ------ 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 |
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| Early-onset Parkinson disease v0.44 | APP | Zornitza Stark Marked gene: APP as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early-onset Parkinson disease v0.44 | APP | Zornitza Stark Gene: app has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.42 | APP | Zornitza Stark Classified gene: APP as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early-onset Parkinson disease v0.42 | APP | Zornitza Stark Gene: app has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early-onset Parkinson disease v0.41 | APP | Zornitza Stark reviewed gene: APP: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Alzheimer disease 1, familial, MIM# 104300; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early-onset Parkinson disease v0.17 | TMEM230 |
Bryony Thompson gene: TMEM230 was added gene: TMEM230 was added to Early onset Parkinson disease. Sources: Expert list Mode of inheritance for gene: TMEM230 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TMEM230 were set to 30804554; 27270108; 28115417; 28017548; 30804555; 30804556; 31323517 Phenotypes for gene: TMEM230 were set to Parkinson disease 21, MIM#616361 Review for gene: TMEM230 was set to AMBER Added comment: A single family segregating a heterozygous missense (p.Arg141Leu) and supporting functional evidence. However, another group found a DNAJC13 variant in the same family also with supporting functional evidence. A stoploss was also identified in 9 Chinese Parkinson disease probands, however it was identified homozygous in 7 of these with no difference in the severity of phenotype. A similar stop loss was identified in a North American PD case. Another missense was identified in an apparently sporadic PD case (p.Tyr92Cys), but was also present in the unaffected mother (age 57 yrs). Another rare missense has been reported in a case with familial PD. The missense reported in a family from Southern Italy is too common in gnomAD v2.1 for a dominant disease (PMID: 31323517 - p.Ile125Met). Sources: Expert list |
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| Early-onset Parkinson disease v0.15 | DCAF17 | Bryony Thompson Added comment: Comment on list classification: Dystonia rather parkinsonism appears to be a feature of this condition and this gene is one the dystonia panel. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early-onset Parkinson disease v0.0 | APP |
Zornitza Stark gene: APP was added gene: APP was added to Early onset Parkinson disease_MelbourneGenomics_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services,Melbourne Genomics Health Alliance Complex Neurology Flagship Mode of inheritance for gene: APP was set to Unknown |
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