Allelic heterogeneity of Proteus syndrome

Area of Science:

• Genetics
• Molecular Biology
• Pathology

Background:

• Proteus syndrome is a rare mosaic disorder characterized by progressive overgrowth.
• Previously, it was solely linked to the mosaic c.49G > A p.(Glu17Lys) variant in the AKT1 gene.
• This AKT1 variant is also implicated in various cancers.

Purpose of the Study:

• To identify the genetic cause in a severe Proteus syndrome case.
• To investigate potential allelic heterogeneity in Proteus syndrome.
• To expand diagnostic approaches for Proteus syndrome.

Main Methods:

• Genetic sequencing of the AKT1 gene in affected tissues.
• Analysis of variant allele fraction in patient-derived fibroblasts.
• Functional assays to assess AKT1 variant activity via AKT phosphorylation.

Main Results:

• A novel mosaic c.49_50delinsAG p.(Glu17Arg) variant in AKT1 was identified in the patient.
• This variant showed constitutive activation of AKT(S473).
• Variant allele fractions varied across different tissues.

Conclusions:

• This study documents allelic heterogeneity for Proteus syndrome.
• The findings suggest that other AKT1 variants can cause Proteus syndrome.
• Genetic testing for Proteus syndrome should include screening for additional AKT1 variants beyond p.(Glu17Lys).