Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome 3 via the CCND2 Gene

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome-3 is a very rare neurological disorder with onset at birth. The major symptoms include enlarged head circumference or macrocephaly, megalencephaly, ventriculomegaly, hydrocephalus, bilateral perisylvian polymicrogyria and postaxial polydactyly in hands and feet, severe developmental delay, severe intellectual disability with absent speech, and inability to walk without aid.  In certain cases, patients may present other neurological symptom such as structural focal epilepsy, drug-resistant epilepsy, seizures, and severe brain malformation extending to both brainstem and cerebellum with hypomyelination. Brain MRI reveals polymicrogyria, hydrocephalus and other brain malformations (Maini et al. 2018. PubMed ID: 29642246; Cappuccio et al. 2019. PubMed ID: 31056854; Mirzaa et al. 2014. PubMed ID: 24705253).  

As megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome can be caused by defects in a number of genes (AKT3, CCND2, and PIK3R2) with variable and overlapping presentations, they can be difficult to diagnose by clinical manifestation and image studies only. An accurate molecular diagnosis is critical for treatment, prognosis, prediction of recurrence risk, as well as future family planning.

CCND2-related megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome-3 is inherited in autosomal dominant manner. Pathogenic variants in CCND2 include missense and nonsense. Large deletions/duplications in the CCND2 locus have not been reported (Human Gene Mutation Database). The vast majority of pathogenic variants are missense with a gain-of-function effect. Almost all cases carry a de novo variant (Mirzaa et al. 2014. PubMed ID: 24705253; Maini et al. 2018. PubMed ID: 29642246). Somatic mosaicism has also been reported (Mirzaa et al. 2014. PubMed ID: 24705253). CCND2 has been cited as a conditionally essential gene for growth of human tissue culture cells (Online Gene Essentiality, ogee.medgenius.info). CCND2 is relatively intolerant to loss-of-function variants (Genome Aggregation Database).

CCND2 encodes cyclin D2, a member of the cyclin D family which is called G1-phase regulators. Overexpression of cyclin D2 results in cell cycle arrest during early development. CCND2 is also a downstream mediator of the PI3K‐AKT pathway. CCND2 is expressed at higher levels in the brains of mouse embryos. A study in zebrafish of cyclin Dx (a member of cyclin D family) suggest that cyclin Dx is required for development of motor neuron progenitors (Lien et al. 2016. PubMed ID: 27323909). CCND2-related disorder is a less common cause of megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (Mirzaa et al. 2014. PubMed ID: 24705253; Maini et al. 2018. PubMed ID: 29642246).

Clinical sensitivity of CCND2 in a large cohort of patients with CCND2-related disorder relevant phenotypes is unavailable in the literature because most studies are case reports. However, pathogenic variants in this gene are a rare cause of megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. Analytical sensitivity should be high.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the CCND2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).