Submission Details

AKT3 has previously been curated by the Brain Malformation GCEP to be definitely causative of overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a difference in the molecular mechanism. Therefore, the following disease entities [overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes] and [microcephaly] have been split into multiple disease entries and were curated separately. AKT3 was first reported in relation to autosomal dominant microcephaly in 2015 (Gai D et al. PMID: 25424989). A proband and his father were found to have hemizygous deletions of the AKT3 gene. The proband was found to have microcephaly, hypotonia, feeding difficulties, developmental delay, and minor dysmorphic features but his father had a normal head circumference and did not have intellectual disability. Reduced penetrance was noted as a possibility, but this evidence was unscored since there were two individuals with the same genotype but vastly different phenotypes. Since 2015, there has been one additional report of a truncating variant in the AKT3 gene resulting in microcephaly (Ciaccio C et al. PMID: 32827175). This gene-disease relationship is supported by experimental evidence. A knock-out mouse model has shown decreased head size due to reduction in cell size and number and reduced mammalian target of rapamycin signaling (Easton et al. PMID:15713641). Based on the few reported cases in humans and animals models the mechanism of pathogenicity is unclear and could be LoF or haploinsufficiency. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification has been approved by the Brain Malformations GCEP on 10/26/2021.