Early onset or syndromic epilepsy

Gene: PPP3CA

I don't know

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Green.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Green List (high evidence)

AD infantile or early childhood epileptic encephalopathy 1 - onset of refractory or multifocal seizures between first weeks and years of life. Myers et al, 2017 - 6 unrelated patients - 5 had seizure onset between 6 weeks and 4 years, 6th had abnormal EEG in absence of overt seizures. EEGs in all showed mutlifocal discharges. 5 de novo het variants - 1 nonsense and 4 missense - 3 in the catalytic domain. Mizuguchi et al, 2018 - looking at patients with IECEE1 init diagnosed as West syndrome - 3 missense and a fs detected - de novo in 3/4 cses where parental samples available.

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Arthrogryposis cleft palate craniosynostosis and impaired intellectual development, 618265; Epileptic encephalopathyinfantile or early childhood, 617711

Publications

• 28942967

Comment on list classification: > 3 cases of de novo variants in this gene associated with Epileptic encephalopathy. Note variants in the catalytic domain result in loss of function and are associated with this phenotype. Variants in the AI domain of the protein are not thought to be loss of function and the clinical phenotype does not always include seizures (PMID: 29432562).

Created: 5 Dec 2018, 3:41 p.m.

Associated with Epileptic encephalopathy, infantile or early childhood, 1 in OMIM and severe Neurodevelopmental Disease with Seizures in Gene2Phenotype (probable).

PMID: 28942967 (Myers et al 2017) 6 unrelated patients with infantile or early childhood epileptic encephalopathy-1 are reported with 5 different de novo heterozygous mutations in PPP3CA. 5 individuals have seizures and all have severe developmental delay. 1 nonsense mutation and 4 missense mutations, 3 of which occurred in the catalytic domain

PMID: 30254215 (Rydzanicz et al 2018) - boy with severe early onset epileptic encephalopathy in whom a novel de novo c.1324C>T (p.(Gln442Ter)) PPP3CA variant was found by whole exome sequencing.

PMID: 30455226 (Qian et al 2018) - girl with de novo frameshift mutation (c.1255_1256del, 105 p.Ser419Cysfs*31) in PPP3CA and seizures since 2 months of age.

PMID: 29432562 (Mizuguchi et al 2018) - report another 6 cases with patients with missense or frameshift variants in PP3CA. 5 of the 6 are confirmed de novo (paternal DNA was not available for the 6th). 3 patients with catalytic domain mutations and a frameshift mutation were in patients with nonsyndromic early onset epileptic encephalopathy (West Syndrome). 2 of the patients had AI domain mutations and these were associated with multiple congenital abnormalities including craniofacial dysmorphism, arthrogryposis and short stature. One also had tractable seizures. Functional studies with fission yeast suggest that the mutations in the catalytic domain are loss of function, while those in the AI domain were associated with the retention of function.

Created: 5 Dec 2018, 3:37 p.m.

Green List (high evidence)

Six unrelated patients reported with 5 de novo variants in this gene and EE.

Created: 19 Aug 2018, 11:31 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Epileptic encephalopathy, infantile or early childhood, 1, MIM#617711

Publications

• 28942967

Variants in this GENE are reported as part of current diagnostic practice