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This summary details the association between CILK1, a gene encoding ciliogenesis-associated kinase 1, and juvenile myoclonic epilepsy. Multiple lines of evidence from case reports and multi-patient studies demonstrate that heterozygous variants in CILK1 segregate with disease in a large family of 37 affected individuals (PMID:29539279) and were identified in approximately 7% of an independent cohort of 310 patients (PMID:29539279).
Genetic evidence strongly supports an autosomal dominant mode of inheritance. Detailed analyses identified several pathogenic variants, including the exemplar variant c.914A>C (p.Lys305Thr), which cosegregated with juvenile myoclonic epilepsy in the family study and was also recurrent in multi-patient evaluations. Additional affected relatives further reinforce the segregation data with 37 affected members showing a clear genotype-phenotype correlation.
Phenotypically, patients present with bilateral tonic-clonic seizures (HP:0002069) characteristic of juvenile myoclonic epilepsy. The clinical observations are supported by robust genetic data where multiple variant types (missense and truncating) in CILK1 have been consistently identified in patients across independent studies (PMID:29539279).
Functional studies provide moderate evidence by demonstrating that CILK1 variants lead to impaired kinase activity and abnormal ciliary localization. Experiments, including in vitro assays and investigations of ciliary structure, have shown that the p.Lys305Thr variant, among others, disrupts cellular processes such as mitosis and neuroblast migration (PMID:32178256).
While one study in murine models reported a lack of overt seizure phenotypes in Cilk1 heterozygous or loss-of-function alleles (PMID:34445580), the preponderance of human genetic and functional data overwhelmingly supports the pathogenic role of heterozygous CILK1 variants in juvenile myoclonic epilepsy.
The integrated evidence from segregation analyses, multi-patient studies, and in vitro functional assays establishes a strong gene-disease association. These findings underscore the clinical utility of assessing CILK1 in the diagnostic workup of juvenile myoclonic epilepsy, with significant implications for both patient management and future therapeutic research.
Key Take‑home Sentence: CILK1 is a robust genetic marker for juvenile myoclonic epilepsy, with heterozygous pathogenic variants driving ciliary dysfunction that underpins the epileptic phenotype.
Gene–Disease AssociationStrongSegregation in 37 affected family members, identification of pathogenic CILK1 variants in multi-patient studies, and concordant functional data support a strong association (PMID:29539279, PMID:32178256). Genetic EvidenceStrongMultiple pathogenic variants, including c.914A>C (p.Lys305Thr), were found to cosegregate with juvenile myoclonic epilepsy in both familial and multi-patient studies, underscoring robust genetic evidence (PMID:29539279). Functional EvidenceModerateFunctional assessments demonstrated impaired kinase activity and altered ciliary localization, which are consistent with the clinical phenotype (PMID:32178256). |