AKT3

Inheritance Pattern: AD

Disease ID:MONDO:0014407

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0011313

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0100283

Submitter: ClinGen

AKT3 was FIRST reported in relation to overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes in 2012 (Poduri et al. 22500628). Several recurrent missense variants have been reported in humans (e.g. E17K) and also copy number gains have been associated with this phenotype, suggestive of a gain-of-function disease mechanism. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Experimental studies have been done on patient cell lines and non-patient derived cells that support this gain of function disease mechanism. In summary, AKT3 has been definitively associated with overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes, and has been upheld over time. Of note this gene is part of a known 1q43q44 deletion syndrome and at least one AKT3 specific deletion has been reported in association with non-overgrowth disease. Therefore, loss-of-function variants in this gene may be associated with a different syndrome as well. This classification was approved by the ClinGen Brain Malformations Gene Curation Expert Panel on 05/25/2021 (SOP Version 7)

Inheritance Pattern: AD

Disease ID:MONDO:0014407

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0014407

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0001149

Submitter: ClinGen

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.

Inheritance Pattern: AD

Disease ID:MONDO:0019375

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0014407

Submitter: Illumina

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.