Submission Details

KCNC1 was first reported in relation to autosomal dominant complex neurodevelopmental disorder (CND) in a family in 2017 (Poirier et al. 2017 PMID: 28145425). Since then, seven variants in 15 families with CND have been reported in four studies. The phenotypes of patients with KCNC1-related CND vary from developmental delay/intellectual disability and hypotonia without seizures to seizures, global developmental delay, hypotonia, and ataxia. The onset varies from birth to 3 years of age. There is a recurrent variant, p.Ala421Val, which is associated with severe phenotypes with myoclonic and generalized tonic clonic seizures and intellectual disability. In addition to CND, KCNC1 is also associated with autosomal dominant progressive myoclonus epilepsy, which is curated separately. The mechanism of pathogenicity appears to be loss of function and dominant negative. Of the 15 reported probands, two had loss-of-function variants inherited from a parent and each received 1.5 pts. Of the remaining 13 families, 12 had de novo variants and received 0.5pt. Of these 12 families de novo variants, 11 had variants with their effects verified by functional studies and received additional 0.5 pts each. In total, maximum score for genetic evidence (12 pts) has been reached. In summary, KCNC1 is definitively associated with autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.