ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

  • 1q43-q44
  • GRCh37/hg19 chr1: 243,651,535-244,006,886
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chr1: 243,488,233-243,851,079
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000001.10) (NC_000001.11)
  • Haploinsufficiency score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity

Haploinsufficiency phenotype comments:

Several papers have described AKT3 deletions in associated with microcephaly. PMID17668379 and PMID 21800092 reviewed 1q43-1q44 deletions in patients with microcephaly (MIC), agenesis of the corpus callosum (ACC) and seizures (SZR). AKT3 haploinsufficiency was thought to be a likely cause of ACC and/or MIC in these patients. In PMID 25424989, the authors described a 1q44 deletion involving only AKT3 in a boy and his father. The boy had microcephaly, hypotonia, feeding difficulties, developmental delay, and minor dysmorphic features. His father was phenotypically within the normal range but had developmental issues earlier in life. The authors supported their findings with further pure AKT3 deletion cases found in Decipher that were inherited. They proposed that a pure AKT3 deletion is more likely to be inherited and has reduced penetrance as compared to larger deletions in the region. Although these papers support a role for deletion of AKT3 as a cause of the microcephaly phenotype, more evidence at the intragenic level is required to conclude that AKT3 is a haploinsufficient gene.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

Some recent reports have suggested a role for duplication of AKT3 in macrocephaly. In PMID 23794269, the authors reported a patient with macrocephaly who had a 3 Mb duplication on 1q43q44 that includes AKT3. The authors also found overlapping partial trisomy cases in the medical literature suggesting an association between AKT3 gain and macrocephaly. These reports correspond with the finding that functionally activating mutations in AKT3 cause Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 (OMIM 615937). In PMID 24700746, the authors described a boy with significant speech delay and relative macrocephaly [head circumference (HC): 54.9 cm (75th centile)]. They detected a microduplication of 1.06Mb present in four copies at 1q43q44 containing AKT3 and five other RefSeq genes (CEP170, LOC339529, MIR4677, SDCCAG8, and ZNF238). They suggested that this additional case was supportive of AKT3 copy gain as a cause of macrocephaly and impaired speech development. However, as isolated whole AKT3 gene duplication or triplication has not yet been described in the medical literature, the role of AKT3 copy gain in causing macrocephaly remains unclear.