ORIGINAL RESEARCH article
Front. Neurosci.
Sec. Neurodevelopment
Volume 19 - 2025 | doi: 10.3389/fnins.2025.1570997
New variants and genotype-phenotype correlation of PPP3CA-related developmental and epileptic encephalopathy
Provisionally accepted- 1Department of Pediatrics, First Hospital, Peking University, Beijing, China
- 2Beijing Children’s Hospital, Capital Medical University, Beijing, Beijing Municipality, China
- 3The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
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Objective To explore the genotypic spectrum and refine the genotype-phenotype correlation of PPP3CA-related developmental and epileptic encephalopathy (DEE).Methods whole-exome sequencing or whole-genome sequencing was performed to all patients. Clinical data of 15 epilepsy patients in current study and 21 epilepsy patients from published studies were collected and analyzed.In this study, 15 patients were identified with 13 de novo PPP3CA variants. Among these, seven frameshift variants and one gene inversion between intron 11 and intron 13 (including exons 12 and 13) were novel. 80% of patients experiencing seizure onset before the age of one. The seizure types observed included epileptic spasms (93.3%), tonic seizures (46.7%), myoclonic seizures (46.7%), focal seizures (40.0%), atypical absence seizures (13.3%), generalized tonic-clonic seizures (6.7%) and myoclonic atonic seizures (6.7%). All patients exhibited global developmental delay. MRI abnormalities were noticed in 9 patients, including widened subarachnoid space, bilateral ventricular width, poor myelination of white matter, and dysplasia of the corpus callosum. 80% specifically diagnosed with infantile epileptic spasms syndrome (IESS). When combining data from this study and published studies, 66.7% of patients experienced seizure onset before the age of one, and 77.8% were diagnosed with IESS.In patients with variants located in the catalytic domain (CD), 45.4% patients exhibited multiple seizure types, while 45.4% patients presented only with epileptic spasms. In contrast, among patients with variants in regulatory domain (RD), 87% had multiple seizure types and only 8.7% had epileptic spasms alone. Additionally, 45.5% of patients with CD variants had comorbid autism spectrum disorders, compared to 13% patients with RD variants. Recurrent variants included p.His92Arg, p.Asp234Glu, p.Glu282Lys and p.Ser419Asnfs*31.This study is the first to report a gene inversion in PPP3CA-related DEE. Patients with only epileptic spasms were more prevalent in those with CD variants, compared to those with RD variants. Conversely, patients with multiple seizure types were more common among those with RD variants. The most frequently diagnosed epileptic syndrome was IESS. Additionally, comorbid ASD were more commonly observed in patients with CD variants than in those with RD variants.
Keywords: PPP3CA, variants, Genotype, phenotype, Developmental and epileptic encephalopathy
Received: 04 Feb 2025; Accepted: 12 May 2025.
Copyright: © 2025 Wang, Ouyang, Niu, Cheng, Yang, Yang, Tan, Liu, Yang and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Yuehua Zhang, Department of Pediatrics, First Hospital, Peking University, Beijing, China
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