CUX2 was first reported in relation to autosomal dominant developmental and epileptic encephalopathy (DEE) in 2012 (Rauch et al., PMID: 23020937). The typical clinical presentation includes intellectual disability and seizure onset in the first year of life, sometimes associated with movement disorders, autism, hypotonia, and abnormal brain MRI (PMID: 29630738). Some individuals were reported to have a Rett-like phenotype including stereotypic movements, breathing abnormalities, and sleep disruption (PMID: 29630738).
A recurrent de novo missense variant (c.1768G>A, p.Glu590Lys) accounts for the majority of published variants in this gene and has been identified in at least 11 probands in four publications (PMIDs: 29630738, 23020937, 29795476, 30842224). Other missense variants (p.Thr642Met and p.Arg1458Gln) were given zero points due to a lack of detailed clinical information and presence of the variants in gnomAD (PMIDs: 31785789, 35571021). Finally, a de-novo p.Thr945Met missense variant was identified in a patient with a history of three febrile seizures, intellectual disability, and developmental delay. It was not scored at this time due to the proband’s milder phenotypic presentation and uncertainty about the association of variants other than p.Glu590Lys with DEE (PMID: 35846140).The mechanism of pathogenicity is currently unknown and there is no experimental evidence available at this time.
In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on the meeting date May 16, 2023 (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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