AKT3 – Microcephaly

Heterozygous loss-of-function of AKT3 has been implicated in primary microcephaly through de novo chromosomal microdeletions encompassing the gene. AKT3 encodes a serine/threonine kinase of the PI3K-AKT pathway, which is critical for neural progenitor proliferation and brain size regulation. Haploinsufficiency appears to underlie reduced head circumference in affected individuals.

In a 3-year-old female with delayed milestones, microcephaly, dysmorphic facial features and corpus callosum hypogenesis, array CGH revealed a 6.5 Mb 1q43q44 deletion including AKT3 (PMID:30410579) and other genes, suggesting AKT3 contributes to the microcephaly phenotype.

A de novo 117 kb microdeletion at 1q43q44 encompassing AKT3 and SDCCAG8 was reported in a 4-year-old boy with microcephaly, neurodevelopmental delay and epilepsy, supporting a pathogenic role for AKT3 haploinsufficiency (PMID:31929334).

In a cohort of four patients with 1q43q44 CNVs, two individuals with 0.16 Mb and 0.18 Mb deletions affecting AKT3 and SDCCAG8 presented with isolated microcephaly without structural brain anomalies, reinforcing AKT3 as a key driver of head size reduction (PMID:30853971).

All reported AKT3 deletions arose de novo, indicating autosomal dominant inheritance with haploinsufficiency as the mechanism. No familial segregation beyond the probands has been described.

Functional studies specifically addressing AKT3 haploinsufficiency in brain development are lacking; however, AKT3 is highly expressed in neural progenitors, and reciprocal AKT3 duplications lead to macrocephaly, providing indirect support for dosage sensitivity.

No conflicting evidence has been reported that disputes the microcephaly association. Additional single-gene point mutations in AKT3 have primarily been linked to brain overgrowth syndromes rather than microcephaly, consistent with opposite dosage effects.

AKT3 haploinsufficiency should be considered in diagnostic evaluation of microcephaly, particularly with 1q43q44 microdeletions. Genomic testing for AKT3 copy number loss informs prognosis and genetic counseling.

Key Take-home: De novo heterozygous deletions of AKT3 cause autosomal dominant microcephaly via haploinsufficiency, making AKT3 copy number analysis essential in microcephaly diagnostics.

References

• Molecular cytogenetics • 2018 • Cytogenomic characterization of 1q43q44 deletion associated with 4q32.1q35.2 duplication and phenotype correlation PMID:30410579
• Clinical dysmorphology • 2020 • Haploinsufficiency of AKT3 gene causing microcephaly and psychomotor delay in a patient with 1q43q44 microdeletion PMID:31929334
• Frontiers in genetics • 2019 • The Role of AKT3 Copy Number Changes in Brain Abnormalities and Neurodevelopmental Disorders: Four New Cases and Literature Review PMID:30853971

Evidence Based Scoring (AI generated)