CCND2 – Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome (MONDO:0019375) is an autosomal dominant neurodevelopmental disorder characterized by prenatal or early-onset brain overgrowth (megalencephaly), cortical malformations (polymicrogyria), distal limb anomalies (postaxial polydactyly), and ventriculomegaly/hydrocephalus. Pathogenic de novo variants in CCND2 (Cyclin D2) localize to the terminal exon, disrupting a glycogen synthase kinase-3β phosphorylation site and resulting in degradation-resistant protein.

1 Assess Clinical Validity

We classify the CCND2–MPPH association as Definitive. Over 10 unrelated probands with de novo CCND2 variants have been reported ([PMID:24705253], [PMID:38700464]). Functional studies, including proteasomal degradation assays and in utero electroporation, consistently reproduce the overgrowth phenotype, fulfilling replication over time with no substantive conflicting reports.

2 Summarise Genetic Evidence

Inheritance is Autosomal dominant with exclusively de novo occurrence; no affected relatives segregate the variants. At least 7 de novo CCND2 probands have been described: recurrent missense and nonsense variants clustering around Thr280–Pro281, e.g., c.842C>T (p.Pro281Leu) ([PMID:24705253]). These reach the ClinGen genetic evidence cap through numerous de novo occurrences and variant clustering.

3 Summarise Functional / Experimental Evidence

The pathogenic mechanism is gain-of-function via cyclin D2 stabilization. Mutant CCND2 proteins resist proteasomal degradation in vitro and accumulate in patient cells and in models of PI3K-AKT activation ([PMID:24705253]). In utero electroporation of mutant CCND2 into embryonic mouse brain increases progenitor proliferation and reduces cell cycle exit, recapitulating human megalencephaly. A de novo nonsense mutation (c.829C>T; p.Gln277Ter) similarly predicts disrupted ubiquitination and protein turnover ([PMID:38700464]).

4 Conflicting Evidence

No studies to date refute or substantially dispute the CCND2–MPPH link. Reciprocal proximal CCND2 variants causing microcephaly represent a distinct inverse-phenotype mechanism, not conflicting with the gain-of-function overgrowth phenotype.

5 Integrate & Conclude

De novo terminal exon CCND2 variants induce cyclin D2 stabilization and drive neural progenitor hyperproliferation, firmly establishing a gain-of-function etiology for MPPH syndrome. The robust genotype–phenotype correlation, combined with functional rescue in model systems, underpins the clinical utility of CCND2 sequencing in individuals presenting with megalencephaly and associated cortical and limb anomalies. Key Take-home: CCND2 gain-of-function variants are a definitive cause of MPPH syndrome, warranting inclusion in diagnostic and potential therapeutic gene panels.

References

• Nature genetics • 2014 • De novo CCND2 mutations leading to stabilization of cyclin D2 cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome PMID:24705253
• DNA and cell biology • 2024 • A de novo Mutation (p.Gln277X) of Cyclin D2 is Responsible for a Child with Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome PMID:38700464

Evidence Based Scoring (AI generated)