Biallelic CACNA2D2 variants were first reported in individuals with epilepsy, global developmental delay, and cerebellar atrophy in 2013 (Edvardson et al., PMID: 23339110). Some patients with biallelic variants in CACNA2D2 have also been reported with motor features like ataxia, dysmetria, and dysarthria in addition to seizures and cerebellar atrophy (PMID: 31402629, 30410802). Given the broad neurodevelopmental phenotypes present in these individuals, we have chosen to curate this gene-disease relationship under the disease term complex neurodevelopmental disorder (MONDO:0100038).
Ten variants (two frameshift, one synonymous, and seven missense) reported in eight probands across seven publications are included in this curation (PMIDs: 23339110, 24358150, 29997391, 30410802, 31402629, 33798445, 31130284). Of note, one individual with compound heterozygous missense and synonymous variants in CACNA2D2 was not scored, as the phase of their variants was not confirmed (PMID: 33798445). This gene-disease relationship is also supported by two mouse models (PMIDs: 11756448, 14660671).
In summary, there is moderate evidence to support the relationship between CACNA2D2 and autosomal recessive complex neurodevelopmental disorder. 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 November 21, 2023 (SOP version 10).
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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