Allelic heterogeneity of Proteus syndrome
- Anna Buser1,
- Marjorie J. Lindhurst1,
- Hannah C. Kondolf1,2,
- Miranda R. Yourick1,3,
- Kim M. Keppler-Noreuil1,4,
- Julie C. Sapp1 and
- Leslie G. Biesecker1
- 1Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
- Corresponding author: lesb{at}mail.nih.gov
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.
- contractures of the large joints
- fibrocystic lung disease
- increased adipose tissue
- lower limb asymmetry
- overgrowth
- upper limb asymmetry
- venous malformation
Footnotes
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↵2 Present affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA
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↵3 Present affiliation: Department of Biology, University of Maryland, College Park, Maryland 20742, USA
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↵4 Present affiliation: Children's National Medical Center, Washington, D.C. 20010, USA
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[Supplemental material is available for this article.]
- Received January 21, 2020.
- Accepted February 19, 2020.
This is a work of the US government.
