The somatic p.T81dup variant in AKT3 gene underlies a mild cerebral phenotype and expands the spectrum including capillary malformation and lateralized overgrowth

Abstract

AbstractHeterozygous germline or somatic variants in AKT3 gene can cause isolated malformations of cortical development (MCDs) such as focal cortical dysplasia, megalencephaly (MEG), Hemimegalencephaly (HME), dysplastic megalencephaly, and syndromic forms like megalencephaly‐polymicrogyria‐polydactyly‐hydrocephalus syndrome, and megalencephaly‐capillary malformation syndrome. This report describes a new case of HME and capillary malformation caused by a somatic AKT3 variant that differs from the common p.E17K variant described in literature. The patient's skin biopsy from the angiomatous region revealed an heterozygous likely pathogenic variant AKT3:c.241_243dup, p.(T81dup) that may affect the binding domain and downstream pathways. Compared to previously reported cases with a common E17K mosaic variant, the phenotype is milder and patients showed segmental overgrowth, an uncommon characteristic in AKT3 variant cases. These findings suggest that the severity of the disease may be influenced not only by the level of mosaicism but also by the type of variant. This report expands the phenotypic spectrum associated with AKT3 variants and highlights the importance of genomic analysis in patients with capillary malformation and MCDs.