Early onset or syndromic epilepsy

Gene: RPS6KC1

Green List (high evidence)

Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update.

Created: 5 Jan 2026, 11:02 a.m. | Last Modified: 5 Jan 2026, 11:02 a.m.

Panel Version: 8.85

PMID:41130203 (2025) reported the identification of biallelic RPS6KC1 variants (both homozygous and compound heterozygous) in 12 individuals from seven independent families and an unrelated 19-week old foetus through whole-exome sequencing. There were 10 different variants identified in total.

The patients presented with a spectrum of conditions including neurodevelopmental delay, subsequent intellectual impairment, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome. The affected foetus had hydrops fetalis and prenatal lethality.

Epilepsy was reported in seven individuals from five families, which included isolated seizures in two unrelated patients and occasional seizures in two patients from a family.

Functional evidence is available from peripheral blood mononuclear cells (PBMCs), HAP1 RPS6KC1-knockdown cells and from Drosophila melanogaster model, which recapitulated the defects observed in individuals with RPS6KC1 variants. Functional studies on PBMCs from the different individuals indicated diminished expression and phosphorylation of RPS6, impacting ribosomal protein synthesis, and a decrease in the known interactors PRDX3 and SPHK1, accompanied by marked repression of the mTOR/PI3K pathway. The study also detected a dysregulation of phosphoinositides and sphingoid base levels in plasma samples from the different individuals. Studies in HAP1 RPS6KC1-knockdown cells suggested that RPS6KC1 may regulate PRDX3 and SPHK1 activities by facilitating their endosome anchoring. In Drosophila melanogaster, the knockdown of CG7156, the RPS6KC1 ortholog, resulted in locomotor dysfunction, defective neuromuscular junctions, reduced lifespan, and decreased mTOR activity. Overexpression of mTOR in this model improved motor function and lifespan.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (accessed on 05 January 2026).
Sources: Literature

Created: 5 Jan 2026, 11:01 a.m. | Last Modified: 5 Jan 2026, 5:42 p.m.

Panel Version: 8.85

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
neurodevelopmental disorder, MONDO:0700092

Publications

• 41130203