The phenotypic and genetic spectrum of AKT3-related neurodevelopmental condition

This study was undertaken to expand the phenotypic and genetic spectrum of AKT3-related neurodevelopmental disorders and to investigate genotype-phenotype correlations. To date, more than 200 patients with AKT3-related disorders have been identified, including those with AKT3 single nucleotide variants and copy number variations affecting the AKT3 gene. Adding our three newly diagnosed patients, the total number of patients with AKT3 single nucleotide variant-related neurodevelopmental disorders is now 61. A total of 20 distinct AKT3 variants have been identified, with p.E17K and p.R465W being potential mutation "hotspots". Approximately 77% (47/61) of the patients experienced macrocephaly, and 81.9% (50/61) had megalencephaly. Seizures were present in 62.3% (38/61) of individuals, and 29.5% (18/61) of patients displayed a thick corpus callosum. In addition, 57 patients with pathogenic or likely pathogenic AKT3 duplications and 175 patients with AKT3 deletions were also reviewed. Among the 68 patients with AKT3 deletions and detailed information reported previously, 97% (66/68) have microcephaly, 72% (49/68) have agenesis or hypoplasia of the corpus callosum, and 63.2% (43/68) suffer from epilepsy. In the 5 patients with pure AKT3 deletion, 100% have microcephaly, while none suffer from epilepsy or abnormal corpus callosum. Patients with AKT3 gain-of-function variants typically present with megalencephaly and structural brain abnormalities. In contrast, AKT3 loss-of-function variants may have a stronger correlation with microcephaly.