Abstracts

Rationale: To explore the phenotypic spectrum and refine the genotype-phenotype correlation of PPP3CA-related DEE.

Methods: Whole-exon sequencing or whole-genome sequencing were performed to all our patients. The clinical data of 14 patients with PPP3CA variations in our cohort and 19 epilepsy patients from published studies were collected and analyzed.

Results: In our cohort, fourteen patients included 12 PPP3CA de novo variants, including 2 missense variants, 9 frameshift variants, and one was a gene inversion between intron 11 and intron 13 (including exons 12 and 13). Seven of these frameshift variants and one gene inversion have not been reported previously. Seizure onset age in 92.9% of patients was within 2 years. Seizure types included epileptic spasms (92.3%), myoclonic seizures (38.5%), tonic seizures (38.5%), focal seizures (30.8%), and generalized tonic-clonic seizures (7.1%). All patients had global developmental delay. Eight patients had brain MRI abnormalities, including widening of the subarachnoid space in the frontotemporal region, poor myelination of the white matter, and dysplasia of the corpus callosum. All patients were diagnosed with DEE, including ten with infantile epileptic spasms syndrome (IESS). Collectively, in our cohort (12 variants) and published studies (15 variants), there were 6 missense variants in the CD domain, 15 frameshift variants, one missense variant and one gene inversion in the RD domain. Most of the patients with variants located in the RD domain had an onset age of less than 6 months, usually showing multiple seizure types and brain MRI abnormalities (70%). However, most of the patients with variants located in the CD domain were mainly epileptic spasms, and had hypotonia (90.9%). The variants, including p.His92Arg (36.4%), p.Asp234Glu (27.3%) and p.Glu282Lys (27.3%), are the hot spot variants.


Conclusions: Seizure onset age in most patients with PPP3CA-related DEE was in infancy. The most common epileptic syndrome was IESS. The majority of PPP3CA-related epilepsy in the RD domain occurs in early infancy, and the types of seizures are diverse, mainly including epileptic spasms, myoclonic seizures and tonic seizures. Patients with variants in the RD domain were more likely to have MRI abnormalities. Conversely, Patients with variants in CD domain mainly presented with IESS, and hypotonia was more common. In addition, our cohort is the first to report gene inversion in PPP3CA-related DEE.


Funding: the National Key R&D Program of China（No. 2023YFC2706301）