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Intellectual disability syndromic and non-syndromic

Gene: C12orf66

Green List (high evidence)
C12orf66 (chromosome 12 open reading frame 66)
EnsemblGeneIds (GRCh38): ENSG00000174206
EnsemblGeneIds (GRCh37): ENSG00000174206
OMIM: 617420, Gene2Phenotype
C12orf66 is in 3 panels

3 reviews

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Comment when marking as ready: New HGNC approved gene name is KICS2
Created: 7 Feb 2025, 6:09 a.m. | Last Modified: 7 Feb 2025, 6:09 a.m.
Panel Version: 1.62
Created: 7 Feb 2025, 6:09 a.m.
Last Modified: 7 Feb 2025, 6:09 a.m.
Panel version: 1.62

Chirag Patel (Genetic Health Queensland)

Green List (high evidence)

11 individuals from 8 families with mild to moderate intellectual disability (11/11), epilepsy (8/11), hearing impairment (3/11), macrocephaly (2/11), facial dysmorphism (6/6).

WES/WGS identified biallelic variants (missense, nonsense, and large deletion) in KICS2 gene (aka C12ORF66). The KICS2 protein is part of the KICSTOR complex which recruits GATOR1 to lysosomes and inhibits mTORC1 activity. Overactivation of the mTORC1 pathway is a recognized cause of several neurodevelopmental disorders.

The variants in the individuals partly affected KICS2 stability, compromised KICSTOR complex formation, and demonstrated a deleterious impact on nutrient-dependent mTORC1 regulation of 4EBP1 and S6K. Phosphoproteome analyses extended these findings to show that KICS2 variants changed the mTORC1 proteome, affecting proteins that function in translation, splicing, and ciliogenesis. Depletion of Kics2 in zebrafish resulted in ciliary dysfunction consistent with a role of mTORC1 in cilia biology.
Created: 5 Feb 2025, 11:40 p.m. | Last Modified: 5 Feb 2025, 11:40 p.m.
Panel Version: 1.62

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Neurodevelopmental disorder MONDO:0700092

Publications

Created: 5 Feb 2025, 11:40 p.m.
Last Modified: 5 Feb 2025, 11:40 p.m.
Panel version: 1.62

Mark Cleghorn (Royal Melbourne Hospital)

I don't know

KICS2 (previously known as C12ORF66)
Rebecca Buchert, Universitatklinikum Tubingen
ESHG talk 2/6/24, unpublished

Proposed ID + epilepsy gene

8 families w 11 affected individuals
Phenotypes: 11/11 ID, 9/11 epilepsy, 3/11 hearing impairment
3/8 homozygous missense variants (p.Asp296Glu, p.Tyr393Cys, p.Tyr393Cys), all highly conserved
1/8 compound het PTC (p.Lys262*) with 1.1Mb deletion
4/8 homozygous PTC (p.Glu3*, p.Gly79Valfs*18, p.Gly79Valfs*18, p.Lys260Asnfs*18)

Gene appears to be involved in mTOR pathway, and cilia function
mTORC1 activity in CRISPR-HEK293T cells – reduced activity in cells w variants above

Zebrafish model: otolith defects, ciliary dysfunction
?not clear if truly mimics phenotype observed in patient cohort described
Sources: Other
Created: 4 Sep 2024, 7:04 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
complex neurodevelopmental disorder MONDO:0100038

Created: 4 Sep 2024, 7:04 a.m.

Panel version: 0.6123

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
Phenotypes
  • complex neurodevelopmental disorder MONDO:0100038
Tags
new gene name
OMIM
617420
Clinvar variants
Variants in C12orf66
Penetrance
unknown
Panels with this gene

History Filter Activity

7 Feb 2025, Gel status: 3

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: c12orf66 has been classified as Green List (High Evidence).

7 Feb 2025, Gel status: 3

Added Tag

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Tag new gene name tag was added to gene: C12orf66.

5 Sep 2024, Gel status: 3

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: c12orf66 has been classified as Green List (High Evidence).

5 Sep 2024, Gel status: 3

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: c12orf66 has been classified as Green List (High Evidence).

4 Sep 2024, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set Phenotypes, Set penetrance

Mark Cleghorn (Royal Melbourne Hospital)

gene: C12orf66 was added gene: C12orf66 was added to Intellectual disability syndromic and non-syndromic. Sources: Other Mode of inheritance for gene: C12orf66 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: C12orf66 were set to complex neurodevelopmental disorder MONDO:0100038 Penetrance for gene: C12orf66 were set to unknown Review for gene: C12orf66 was set to AMBER