Most PIK3CA mutations identified to date are Gain of Function (GoF) mutations known to be associated with PI3K-AKT-MTOR pathway hyperactivity. Most identified PIK3CA mutations are postzygotic (or mosaic), with a small number of germline (constitutional) mutations identified. Preliminary genotype-phenotype correlations suggest that phenotypes depend on tissue distribution, levels of mosaicism and type of PIK3CA mutation with three general correlations identified:
- The most severe GOF mutations are associated with severe overgrowth and cellular dysplasia causing HMEG, FCD, CLOVES, or severe focal phenotypes (e.g. vascular or lymphatic malformations).
- Intermediate GOF mutations are, with rare exceptions, associated with MEG and PMG (i.e. MCAP syndrome), and rarely other phenotypes (e.g. vascular or lymphatic malformations).
- The least severe GOF mutations are associated with diffuse MEG with apparently normal gyral pattern.