Activity
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| Early onset or syndromic epilepsy v8.85 | RPS6KC1 |
Achchuthan Shanmugasundram changed review comment from: 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 recapitulated the defects observed in individuals with RPS6KC1 variants. 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; to: 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 |
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| Early onset or syndromic epilepsy v7.63 | C12orf66 |
Arina Puzriakova gene: C12orf66 was added gene: C12orf66 was added to Early onset or syndromic epilepsy. Sources: Literature new-gene-name, Q1_25_ promote_green tags were added to gene: C12orf66. Mode of inheritance for gene: C12orf66 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C12orf66 were set to 39824192 Phenotypes for gene: C12orf66 were set to Intellectual developmental disorder, autosomal recessive 83, OMIM:621100 Review for gene: C12orf66 was set to GREEN Added comment: This gene is associated with a relevant phenotype in OMIM (MIM# 621100) - PMID: 39824192 (2025) - biallelic variants in KICS2 in 11 individuals from 8 families with intellectual disability. All affected individuals had mild to severe intellectual disability, with 8 individuals also presenting with seizures and 3 (2 families) with hearing impairment. Functional studies in cell culture and zebrafish models provided evidence of pathogenicity, showing impaired mTORC1 regulation and effects on ciliogenesis. Sources: Literature |
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| Early onset or syndromic epilepsy v4.148 | MTOR | Sarah Leigh Publications for gene: MTOR were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v4.147 | MTOR | Sarah Leigh Phenotypes for gene: MTOR were changed from Focal cortical dysplasia, type II, somatic to Smith-Kingsmore syndrome, OMIM:616638; macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, MONDO:0014716; Focal cortical dysplasia, type II, somatic, OMIM:607341isolated focal cortical dysplasia type II, MONDO:0011818 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v4.40 | RHEB | Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to support an association with epilepsy; however, it is worth noting that variants are brain-specific somatic. Still adding to this panel as other somatic mosaic genes (e.g. GNAQ, MTOR, TSC1, TSC2) are included.; to: Comment on list classification: There is sufficient evidence to support an association with epilepsy; however, it is worth noting that variants are brain-specific somatic. Still adding to this panel as other somatic mosaic genes are included (e.g. GNAQ, MTOR, TSC1, TSC2). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v4.40 | RHEB | Arina Puzriakova changed review comment from: Comment on list classification: The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.; to: Comment on list classification: There is sufficient evidence to support an association with epilepsy; however, it is worth noting that variants are brain-specific somatic. Still adding to this panel as other somatic mosaic genes (e.g. GNAQ, MTOR, TSC1, TSC2) are included. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.191 | MTOR | Rebecca Foulger Source Wessex and West Midlands GLH was added to MTOR. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.190 | MTOR | Rebecca Foulger Source NHS GMS was added to MTOR. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.189 | MTOR | Rebecca Foulger reviewed gene: MTOR: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.188 | MTOR | Tracy Lester reviewed gene: MTOR: Rating: GREEN; Mode of pathogenicity: ; Publications: 26542245, 28892148 ; Phenotypes: Focal cortical dysplasia, type II, somatic,607341, Smith-Kingsmore syndrome,616638; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy | MTOR | Sarah Leigh Added gene to panel | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||