Genetic Epilepsy

Gene: C12orf66

Comment when marking as ready: HGNC approved name is KICS2

Created: 7 Feb 2025, 6:08 a.m. | Last Modified: 7 Feb 2025, 6:08 a.m.

Panel Version: 1.108

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.
Sources: Literature

Created: 5 Feb 2025, 11:38 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Neurodevelopmental disorder MONDO:0700092

Publications

• PMID: 39824192