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Allelic heterogeneity of Proteus syndrome.

ABSTRACT: Proteus syndrome is a mosaic disorder that can cause progressive postnatal overgrowth of nearly any organ or tissue. To date, Proteus syndrome has been exclusively associated with the mosaic c.49G > A p.(Glu17Lys) pathogenic variant in AKT1, a variant that is also present in many cancers. Here we describe an individual with severe Proteus syndrome who died at 7.5 yr of age from combined parenchymal and restrictive pulmonary disease. Remarkably, this individual was found to harbor a mosaic c.49_50delinsAG p.(Glu17Arg) variant in AKT1 at a variant allele fraction that ranged from <0.01 to 0.46 in fibroblasts established from an overgrown digit. This variant was demonstrated to be constitutively activating by phosphorylation of AKT(S473). These data document allelic heterogeneity for Proteus syndrome. We recommend that individuals with a potential clinical diagnosis of Proteus syndrome who are negative for the p.(Glu17Lys) variant be tested for other variants in AKT1.

SUBMITTER: Buser A

PROVIDER: S-EPMC7304363 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Allelic heterogeneity of Proteus syndrome.

Buser Anna A Lindhurst Marjorie J MJ Kondolf Hannah C HC Yourick Miranda R MR Keppler-Noreuil Kim M KM Sapp Julie C JC Biesecker Leslie G LG

Cold Spring Harbor molecular case studies 20200612 3

Proteus syndrome is a mosaic disorder that can cause progressive postnatal overgrowth of nearly any organ or tissue. To date, Proteus syndrome has been exclusively associated with the mosaic c.49G > A p.(Glu17Lys) pathogenic variant in <i>AKT1</i>, a variant that is also present in many cancers. Here we describe an individual with severe Proteus syndrome who died at 7.5 yr of age from combined parenchymal and restrictive pulmonary disease. Remarkably, this individual was found to harbor a mosaic ...[more]

PMID: 32327430

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