Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome 2 via the AKT3 Gene

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome-2 is a rare, early onset neurological disorder. The major symptoms include enlarged head circumference or macrocephaly, megalencephaly, ventriculomegaly, hydrocephalus, cortical malformations, heterotopia, polymicrogyria, severe intellectual disability, seizures, and postaxial polydactyly in hands and feet. Patients also present other minor symptoms such as a mild connective tissue dysplasia, skin hyperextensibility and vascular malformations. Brain MRI reveals megalencephaly, ventriculomegaly and other brain malformations (Rivière et al. 2012. PubMed ID: 22729224; Nellist et al. 2015. PubMed ID: 25523067; Negishi et al. 2017. PubMed ID: 28086757; Nakamura et al. 2014. PubMed ID: 23745724; Alcantara et al. 2017. PubMed ID: 28969385).  

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, as well as future family planning.

AKT3-related megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome-2 is inherited in autosomal dominant manner. Pathogenic variants in AKT3 include missense, large deletions and duplications (Human Gene Mutation Database). Almost all cases carry a de novo variant (Alcantara et al. 2017. PubMed ID: 28969385; Rivière et al. 2012. PubMed ID: 22729224). Somatic mosaicism has been associated with hemimegalencephaly (Alcantara et al. 2017. PubMed ID: 28969385). AKT3 is relatively intolerant to both missense and loss-of-function variants (Genome Aggregation Database).

AKT3 encodes AKT serine/threonine kinase 3, a member of the AKT protein family which is one of the core components of the phosphatidylinositol-3-kinase (PI3K)-AKT- -mTOR pathway in vascular, limb and brain development (Rivière et al. 2012. PubMed ID: 22729224; Negishi et al. 2017. PubMed ID: 28086757). Functional analysis of the pathogenic variants in AKT3 showed a significant increase of catalytic kinase activity. This is consistent with a mechanism that the elevated PI3K-AKT-MTOR signaling results in brain overgrowth disorders (Alcantara. 2017. PubMed ID: 28969385). This is also supported by a knock out mouse model of Akt3-/- which presented a selective 20% decrease in brain size (Easton et al. 2005. PubMed ID: 15713641). AKT3-related disorder is a relatively rare cause of megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (Rivière et al. 2012. PubMed ID: 22729224; Alcantara et al. 2017. PubMed ID: 28969385).

Clinical sensitivity of AKT3 in a large cohort of patients with AKT3-related 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 AKT3 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).