CAMK2A was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2017 (Kury et al., PMID: 29100089). Variable clinical manifestations, including mild to severe intellectual disability, delayed psychomotor development, delayed or absent speech, delayed walking, seizures, dysmorphic features and behavioural, psychiatric manifestations such as autism spectrum disorders, aggressive behaviour, and hyperactivity characterise probands with CAMK2A-related complex neurodevelopmental disorder.
Sixteen variants (missense, in-frame indel, nonsense and splice-site variants) that have been reported in eighteen probands in three publications (PMIDs: 29100089, 29560374, 37510258) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is thought to be both gain-of-function and loss-of-function (PMIDs 29100089, 29560374). Overall, functional and clinical data suggest that gain-of-function variants that affect the autoregulatory domain correlate with a more severe phenotype. This gene-disease relationship is also supported by in vitro phosphorylation of the CAMK2A protein and its impact on neuron migration, with both increased or decreased phosphorylation leading to reduced neuron migration (PMID: 29100089).
In summary, there is definitive evidence supporting the relationship between CAMK2A and autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism GCEP on the meeting date October 15, 2024 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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