Submission Details

Autosomal dominant

02/11/2019

The AKT3 gene is located on chromosome 1 at 1q43-q44 and encodes the AKT serine/threonine kinase 3 protein, which is associated with regulation of metabolism, proliferation, cell survival, growth and angiogenesis. It also critical for brain development. The AKT3 gene was first reported in relation to autosomal dominant megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome in 2012 (22729224: Riviere et al. 2012). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least five probands in four publications (22729224: Riviere et al. 2012); 23745724: Nakamura et al. 2014); 25523067: Nellist et al. 2015); 28190287: Takagi et al. 2017). In these cases, the variants reported were de novo and variant level evidence suggested a gain in function. More case level evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) was reached. This gene-disease relationship is supported by expression data showing that AKT3 is the predominant AKT paralog in the brain and a AKT3 knockout mouse model, in which homozygous null mice were observed to have ~20 % smaller brains than their wildtype litter mates, consistent with a AKT3’s role in regulating brain size (15713641: Easton et al. 2005). In summary, AKT3 is definitively associated with autosomal dominant megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome.

22729224 23745724 25523067 28190287 15713641