Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome 1 via the PIK3R2 Gene

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome-1 is a rare and early onset neurological disorder. The major symptoms include macrocephaly, megalencephaly, ventriculomegaly, hydrocephalus, cortical malformations, polymicrogyria, focal pachygyria, focal cortical dysplasiacorpus, callosum hyperplasia, profound intellectual disability, seizures and postaxial polydactyly. In certain cases, patients also present other symptoms such as duplicated kidneys, heart malformations and Asperger-like features. Brain MRI reveals megalencephaly, ventriculomegaly and other brain malformations (Mirzaa et al. 2015. PubMed ID: 26520804; Nakamura et al. 2014. PubMed ID: 23745724; Negishi et al. 2017. PubMed ID: 28086757; Terrone et al. 2016. PubMed ID: 26860062).   

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, the disorder 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.

PIK3R2-related megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome-1 is inherited in autosomal dominant manner. Pathogenic variants in PIK3R2 include missense and small and large deletions, with missense being the majority (Human Gene Mutation Database). De novo variants are common (Terrone et al. 2016. PubMed ID: 26860062; Quinlan-Jones et al. 2019. PubMed ID: 30293990). Somatic mosaicism of PIK3R2 has also been documented in several studies (Tapper et al. 2014. PubMed ID: 24497998; Mirzaa et al. 2015. PubMed ID: 26520804). In one study, 12 patients had constitutional pathogenic variants, whereas 8 patients had mosaic pathogenic variants (Mirzaa et al. 2015. PubMed ID: 26520804). PIK3R2 has been cited as a conditionally essential gene for growth of human tissue culture cells (Online Gene Essentiality, ogee.medgenius.info).

PIK3R2 encodes phosphatidylinositol 3-kinase, regulatory subunit 2, a core component 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 pathogenic variants in PIK3R2 showed a significant increase of Phospho-S6 protein activity. The Phospho-S6 protein is an indicator of pathway activation, because it is downstream of the mTOR pathway. This is consistent with the mechanism that elevated PI3K-AKT-MTOR signaling results in brain overgrowth disorders (Negishi et al. 2017. PubMed ID: 28086757). In addition, knock out mice model showed enhanced T cell proliferation due to lack of functional PIK3R2 gene (Deane et al. 2004. PubMed ID: 15153476). PIK3R2-related disorder is a relatively rare cause of megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (Rivière et al. 2012. PubMed ID: 22729224; Negishi et al. 2017. PubMed ID: 28086757).

Clinical sensitivity of PIK3R2 in a large cohort of patients with PIK3R2-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 PIK3R2 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.

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).