Figure 4.

Diagram showing the spectrum of AKT3-associated phenotypes. Several groups of partially overlapping developmental brain disorders are associated with AKT3 mutations that include the following phenotypes (i) focal malformations of cortical development that are highly segmental [e.g. focal cortical dysplasia (FCD), hemimegalencephaly (HMEG), dysplastic megalencephaly DMEG; orange]; (ii) bilateral polymicrogyria (PMG) (purple) with or without ventriculomegaly or hydrocephalus (VMEG-HYD; light purple), and heterotopia (HET; blue); (iii) diffuse megalencephaly with intellectual disability (ID) and/or autistic features (AUT) with subtle or no cortical dysplasia (green). *Of note, MCAP and MPPH fit within the second group of AKT3-related disorders, from the brain phenotype perspective. MCAP can be further clinically distinguished by somatic findings (somatic overgrowth, vascular or lymphatic abnormalities), and MPPH by the occurrence of polydactyly in a subset of affected individuals. A general molecular diagnostic workflow for megalencephaly has been proposed (Supplementary Fig. 1). OFC = orbitofrontal cortex.