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Genetic epilepsy syndromes

Gene: PPP2CA

Green List (high evidence)

PPP2CA (protein phosphatase 2 catalytic subunit alpha)
EnsemblGeneIds (GRCh38): ENSG00000113575
EnsemblGeneIds (GRCh37): ENSG00000113575
OMIM: 176915, Gene2Phenotype
PPP2CA is in 3 panels

4 reviews

Rebecca Foulger (Genomics England curator)

I don't know

Kept rating as Green based on Green post-Webex review from Helen Lord.
Created: 9 Sep 2019, 10:39 a.m. | Last Modified: 9 Sep 2019, 10:39 a.m.
Panel Version: 1.320
Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.
Created: 5 Sep 2019, 2:26 p.m. | Last Modified: 5 Sep 2019, 2:26 p.m.
Panel Version: 1.262

Helen Lord (Oxford Medical Genetics Laboratories)

Green List (high evidence)

AD NEDLBA. Reynhout et al, 2019 - 16 unrelated patients aged between 1.5 to 23 years with a neurodev disorder. Patients had global dev delay, Epilepsy in 12 patients - 10 variable seizures incl focal, generalised and febrile, 1 eith severe epileptic encephalopathy and 1 with refractory seizures assoc with hypsarrhythmia on EEG. de novo het variants detected, inco nonsense, fs and missense distributed throughout the gene. Another patient with a similar phenotype had a de nov het 120kb del incl exon 1 of PPP2CA and part of the neighbouring gene CDKL3. In vitro studies of HEK293 cells transfected with selected mutations including missense variants confirmed decrased or absent protein levels, consistent with haploinsufficiency as the main pathogenic mechanism.
Created: 5 Sep 2019, 2:22 p.m. | Last Modified: 5 Sep 2019, 2:22 p.m.
Panel Version: 1.261

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Catherine Snow (Genomics England)

Expert review on PPP2CA by Konstantinos Varvagiannis. Reynhout et al. (PMID:30595372) reported on 16 individuals with heterozygous pathogenic PPP2CA variants. Frequent features included feeding difficulties, hypotonia, developmental delay (16/16) with intellectual disability. Seizures are seen in 9 of 16 individuals. There are sufficient individuals to rate PPP2CA as Green, there is also phenotype support as PPP2CA is in OMIM and probable in Gene2Phen.
Created: 27 Jun 2019, 2:09 p.m. | Last Modified: 27 Jun 2019, 2:15 p.m.
Panel Version: 0.43

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Reynhout et al. (doi.org/10.1016/j.ajhg.2018.12.002 - PMID not available) report on 16 individuals with heterozygous pathogenic PPP2CA variants.

Frequent features included feeding difficulties, hypotonia, developmental delay (16/16) with intellectual disability (probably 15/16 - a single individual developped cognitive dysfunction following a psychotic episode), language impairment, behavioral problems, seizures (10/16), brain abnormalities and variable other features.

The variants reported included 3 nonsense mutations, 1 frameshift, 1 duplication of one amino acid, 9 missense variants (of which one was observed twice and 2 affected Asp223) as well as a partial gene deletion (spanning also CDKL3).

Various mechanisms seemed to explain the effect of the different variants - among others - haploinsufficiency for some or a dominant negative effect for others, etc.

Type 2A protein phosphatases (PP2As) comprise 3 subunits, a catalytic C-type subunit (PPP2CA encodes the Cα subunit), a scaffolding A-type subunit as well as a regulatory B-type subunit important for their function. Impairment of PP2A-B56δ (encoded by PPP2R5D) binding/functionality was suggested for most of the variants. Similar dysfunction has been observed - among others - upon loss of one functional allele of PPP2R1A.

The effect of 2 variants affecting Asp223 (Asp223Val and Asp233His) was unclear as they largely behaved similar to wild-type in various functional assays. The authors argue that contribution of mutations in other genes could not be ruled out for the individuals harboring these variants, as could also be the case for the subject with disruption of (also) CDKL3.

The authors note overlapping phenotype with PPP2R1A and PPP2R5D-related ID (MIM 616362 and 616355 respectively).

Brain-specific Ppp2ca knockout in mice (PMID: 29274472) resulted in morphological and behavioral abnormalities partly overlapping with features observed in individuals with PPP2CA mutations. However mice heterozygous for null mutations have not been phenotypically examined (PMID: 30030003).
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PPP2CA is not associated with any phenotype in OMIM, nor in G2P.
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As a result, PPP2CA can be considered for inclusion in this panel as green (or amber).
Sources: Literature
Created: 28 Dec 2018, 6:57 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Feeding difficulties; Muscular hypotonia; Global developmental delay; Intellectual disability; Language impairment; Seizures; Abnormality of nervous system morphology

Publications

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Wessex and West Midlands GLH
  • NHS GMS
  • Expert Review
  • Expert Review Green
  • Expert Review Green
  • Expert Review
Phenotypes
  • Abnormality of nervous system morphology
  • Seizures
  • Language impairment
  • Muscular hypotonia
  • Feeding difficulties
  • Intellectual disability
  • Neurodevelopmental disorder and language delay with or without structural brain abnormalities, 618354
  • Global developmental delay
OMIM
176915
Clinvar variants
Variants in PPP2CA
Penetrance
unknown
Publications
Panels with this gene

History Filter Activity

17 Sep 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source Wessex and West Midlands GLH was added to PPP2CA.

17 Sep 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source NHS GMS was added to PPP2CA.

22 Jul 2019, Gel status: 3

Added New Source, Added New Source, Set Phenotypes, Set publications, Status Update

Catherine Snow (Genomics England)

Source Expert Review Green was added to PPP2CA. Source Expert Review was added to PPP2CA. Added phenotypes Neurodevelopmental disorder and language delay with or without structural brain abnormalities, 618354 for gene: PPP2CA Publications for gene PPP2CA were changed from 29274472; 30030003 to 29274472; 30030003; 30595372 Rating Changed from No List (delete) to Green List (high evidence)

28 Dec 2018, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

gene: PPP2CA was added gene: PPP2CA was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: PPP2CA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: PPP2CA were set to 29274472; 30030003 Phenotypes for gene: PPP2CA were set to Feeding difficulties; Muscular hypotonia; Global developmental delay; Intellectual disability; Language impairment; Seizures; Abnormality of nervous system morphology Penetrance for gene: PPP2CA were set to unknown Review for gene: PPP2CA was set to GREEN