CCND2 (Cyclin D2) was first reported in relation to autosomal dominant Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus syndrome in 2014 (Mirzaa et al., PMID: 24705253). CCND2 is a gene that encodes for a protein that functions in the regulation of CDK kinases in the cell cycle and is regulated by the PI3K-AKT pathway. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found evidence in molecular mechanism and phenotypic variability, therefore the following disease entities have been split into two disease entities, microcephaly, short stature & developmental delay and Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH) 3 (OMIM 615938). The split curation for microcephaly, short stature & developmental delay will be discussed separately.
9 variants (8 missense, 1 nonsense), that have been reported in 17 probands in 7 publications (PMIDs: 24705253, 31056854,28941273, 29642246, 33634562, 24705253) are included in this curation. More evidence is available in the literature (PMIDs:38700464, 31957131, 32371413, 33144682, 37486637, 36939041), however the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is gain of function. Specifically, mutations in the PEST motif of exon 5 lead to decreased protein degradation and increased protein stability. (PMID: 24705253). The Mouse Genome Informatics (MGI) database lists several CCND2 mutations and alleles; however, none of the corresponding mouse strains met the criteria to be considered non-human model organisms supporting a gene-disease relationship for CCND2.
In summary, there is definitive evidence supporting the relationship between CCDN2 and autosomal dominant megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. 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 Brain Malformations GCEP on the meeting date May 27th, 2025 (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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