Variants in CSNK2A1 were first reported in relation to an autosomal dominant form of syndromic intellectual disability, also known as Okur-Chung neurodevelopmental disorder, in 2016 (Okur et al., PMID: 27048600). Clinical features in reported probands include global developmental delay, intellectual disability, abnormal facial shape, short stature, behavioral abnormalities, hypotonia, sleep disturbance, seizures, ataxia, as well as brain, heart, skin, and pituitary gland abnormalities. Most reported variants are missense, and the rest are nonsense, splice and frameshift variants; the majority are de novo. Fourteen unique missense and two protein truncating variants that have been reported in six publications (PMIDs: 27048600, 28725024, 29383814, 30655572, 31729156, 34038195) are included in this curation. Though functional data is available to support many of the variants, it has been scored as experimental evidence rather than at the level of each individual variant. More evidence is available in the literature (PMID: 2961923), but the maximum score for genetic evidence has been reached. Of note, five of the reported missense variants are recurrent.
This gene-disease relationship is also supported by experimental evidence, including functional studies, biochemical function, protein interaction and a mouse model. CSNK2A1 encodes CK2α, a serine/threonine protein kinase. Variants in CSNK2A1 have been shown to cause a decrease in the kinase activity of the CK2α protein and changes in the alpha subunit’s subcellular localization (PMID: 33944995). CK2α interacts with the CK2β subunit encoded by CSNK2B, which is also implicated in syndromic intellectual disability (Poirier-Bienvenu neurodevelopmental syndrome).
In summary, there is definitive evidence supporting the relationship between CSNK2A1 and autosomal dominant syndromic intellectual disability. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on June 15, 2022 (SOP Version 9).
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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