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

Abstract

Heterozygous 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.

Epilepsy with faint capillary malformation or reticulated telangiectasia associated with mosaic AKT3 pathogenic variants

“…Focal cortical dysplasia (FCD) belongs to the broader spectrum of malformations of cortical development (MCD), and it has also been associated with pathogenic variants in genes belonging to the PI3K–AKT–mTOR pathway. However, CM has been rarely associated with FCD (Jansen et al, 2015; Luca et al, 2023; Pirozzi et al, 2022). In other MCDs, such as megalencephaly‐capillary malformation (M‐CM) and megalencephaly‐pachygyria‐polydactyly‐hydrocephalus syndrome, CMs or vascular malformations of the skin are observed more often (D'Gama et al, 2017; Mirzaa et al, 2012; Pirozzi et al, 2022; Rivière et al, 2012).…”