Early onset or syndromic epilepsy

Gene: PPP2R1A

Green List (high evidence)

Comment on list classification: There are numerous individuals reported in literature with heterozygous PPP2R1A variants and a neurodevelopmental syndrome, which includes epilepsy in 40-50% of patients. Hence, this gene should be promoted to Green for Early onset or syndromic epilepsy at the next update.

Created: 13 Mar 2026, 11:53 a.m. | Last Modified: 13 Mar 2026, 11:53 a.m.

Panel Version: 8.147

PMID: 33106617 Lenaerts et al., 2021
Report of 30 individuals with 16 different de novo variants in PPP2R1A. Shared phenotype: developmental delay (97%), hypotonia (93%), hypermobile joints (58%), CC hypoplasia/agenesis (56%), epilepsy (38%), macrocephaly (38%). Macrocephaly and epilepsy were mutually exclusive. Intellectual disability ranged from mild to severe, based on functional effects of each variant.

Functional evidence: HEK293T cells transfected with PPP2R1A mutants - variants from patients with less severe ID, no seizures, and sometimes macrocephaly typically showed normal B55α and STRN3 binding, while more severe ID, seizures, and sometimes microcephaly correlated with lost B55α binding and increased STRN3 binding.

17/35 (49%) of patients with PPP2R1A-Related Neurodevelopmental Disorder presented with epilepsy according to GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK580243/)

PPP2R1A is now associated with AD Houge-Janssens syndrome 2, OMIM:616362 (OMIM accessed 13th Mar 2026). PPP2R1A is Definitve in ClinGen for an AD complex neurodevelopmental disorder (Nov 2022).
Sources: Literature

Created: 13 Mar 2026, 11:48 a.m. | Last Modified: 13 Mar 2026, 11:58 a.m.

Panel Version: 8.147

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Houge-Janssens syndrome 2, OMIM:616362; Houge-Janssens syndrome 2, MONDO:0014605

Publications

• 33106617