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Intellectual disability v9.217 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. Moderate intellectual disability was reported in nine individuals rom four unrelated families.

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. Moderate intellectual disability was reported in nine individuals rom four unrelated families.

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
Intellectual disability v4.53 HK1 Arina Puzriakova Tag Q3_22_MOI was removed from gene: HK1.
Tag Q3_22_NHS_review was removed from gene: HK1.
Intellectual disability v4.53 HK1 Arina Puzriakova commented on gene: HK1
Intellectual disability v4.52 HK1 Arina Puzriakova Source NHS GMS was added to HK1.
Mode of inheritance for gene HK1 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v3.1756 HK1 Arina Puzriakova Phenotypes for gene: HK1 were changed from Neurodevelopmental disorder with visual defects and brain anomalies, OMIM:618547; neurodevelopmental disorder with visual defects and brain anomalies, MONDO:0032807 to Neurodevelopmental disorder with visual defects and brain anomalies, OMIM:618547
Intellectual disability v3.1729 HK1 Eleanor Williams Tag Q3_22_MOI tag was added to gene: HK1.
Tag Q3_22_NHS_review tag was added to gene: HK1.
Intellectual disability v3.1729 HK1 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the MOI as biallelic for now but with the recommendation of changing to monallelic following GMS review.
Intellectual disability v3.1729 HK1 Eleanor Williams Mode of inheritance for gene: HK1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.1728 HK1 Eleanor Williams Phenotypes for gene: HK1 were changed from Hemolytic anemia due to hexokinase deficiency, 235700; Neuropathy, hereditary motor and sensory, Russe type, 605285; Abnormal muscle tone; Global developmental delay; Intellectual disability; Visual impairment; Neurological speech impairment; Ataxia to Neurodevelopmental disorder with visual defects and brain anomalies, OMIM:618547; neurodevelopmental disorder with visual defects and brain anomalies, MONDO:0032807
Intellectual disability v3.1727 HK1 Eleanor Williams commented on gene: HK1: As noted by Tracy Lester, the cases reported by Okur et al. 2019 - PMID: 30778173 are have heterozygous de novo variants in HK1 and a phenotype of developmental delay, intellectual disability, structural brain abnormality, and visual impairments, therefore the mode of inheritance should be changed from biallelic to monoallelic.
Intellectual disability v3.1720 HK1 Tracy Lester reviewed gene: HK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30778173; Phenotypes: Intellectual disability, developmental delay, delayed speech and language, learning disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v2.949 HK1 Ivone Leong Classified gene: HK1 as Green List (high evidence)
Intellectual disability v2.949 HK1 Ivone Leong Added comment: Comment on list classification: Promoted from red to green. This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. There are sufficient cases for this gene to be promote to green status. Variants on the 5' end of the gene have been associated with neuropathy, hereditary motor and sensory, Russe type.
Intellectual disability v2.949 HK1 Ivone Leong Gene: hk1 has been classified as Green List (High Evidence).
Intellectual disability v2.948 HK1 Ivone Leong Added comment: Comment on mode of pathogenicity: A gain of function effect is presumed to cause disease.
Intellectual disability v2.948 HK1 Ivone Leong Mode of pathogenicity for gene: HK1 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Intellectual disability v2.947 HK1 Ivone Leong Phenotypes for gene: HK1 were changed from Hemolytic anemia due to hexokinase deficiency, 235700; Neuropathy, hereditary motor and sensory, Russe type, 605285 to Hemolytic anemia due to hexokinase deficiency, 235700; Neuropathy, hereditary motor and sensory, Russe type, 605285; Abnormal muscle tone; Global developmental delay; Intellectual disability; Visual impairment; Neurological speech impairment; Ataxia
Intellectual disability v2.946 HK1 Ivone Leong Publications for gene: HK1 were set to
Intellectual disability v2.945 HK1 Ivone Leong Tag missense tag was added to gene: HK1.
Intellectual disability v2.742 HK1 Konstantinos Varvagiannis reviewed gene: HK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30778173, 28135719; Phenotypes: Abnormal muscle tone, Global developmental delay, Intellectual disability, Visual impairment, Neurological speech impairment, Ataxia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability HK1 BRIDGE consortium edited their review of HK1
Intellectual disability HK1 BRIDGE consortium edited their review of HK1
Intellectual disability HK1 Louise Daugherty classified HK1 as amber
Intellectual disability HK1 Louise Daugherty commented on HK1
Intellectual disability HK1 BRIDGE consortium reviewed HK1