• Test code: 04502
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top EDTA tube (K2EDTA or K3EDTA)
  • Alternate specimens:
    Saliva, assisted saliva, buccal swab and gDNA
  • Sample requirements
  • Request a sample kit

Invitae Proteus Syndrome Test

Test description

The Invitae Proteus syndrome test analyzes the AKT1 gene that is associated with Proteus syndrome, an overgrowth syndrome caused by a mosaic pathogenic AKT1 variant, c.49G>A (p.Glu17Lys). Proteus syndrome is characterized by asymmetric overgrowth of bone, skin and other tissues.

The clinical utility of germline testing for AKT1 is expected to be reduced as the diagnosis of Proteus syndrome is based on the identification of a single known somatic mosaic variant in AKT1 and germline mutations in AKT1 are hypothesized to be lethal. In individuals who meet diagnostic criteria (PMID: 23992099), DNA extracted from the affected tissue is recommended; however, deletion/duplication analysis is not guaranteed for this sample type. Deletion/duplication analysis will be attempted for all DNA specimens; however, the success rate varies depending on specimen quality.

Genetic testing of this gene may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant can inform recurrence-risk assessment and genetic counseling.

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Primary panel (1 gene)

Alternative tests to consider

Many clinical features of Proteus syndrome overlap with other overgrowth syndromes. The Invitae Overgrowth and Macrocephaly Syndromes panel is intended to aid in the identification of a possible genetic cause for patients who present with a set of symptoms that include abnormal excessive height and/or weight and/or macrocephaly (>2 standard deviations). Onset may be prenatal or postnatal. Overgrowth may manifest in a symmetric or asymmetric pattern, and may include additional features such as developmental delay, intellectual disability, seizures, behavioral abnormalities, and dysmorphic features. Increased risk of cancer is commonly associated with many of these syndromes.

Please note, that the recommended specimen type for the Invitae Proteus syndrome test is extracted DNA; however, deletion/duplication analysis is not guaranteed with this specimen type if considering both the Invitae Overgrowth and Macrocephaly Panel and the Invitae Proteus syndrome test. If both tests are clinically indicated, it is recommended to submit two test requisitions and two sample types (extracted DNA and blood). Additional charges apply.

  • Proteus syndrome

Proteus syndrome is a highly variable, mosaic condition that is characterized by asymmetric and disproportionate overgrowth of the body, connective tissue and epidermal nevi, vascular malformations and dysregulated adipose tissue. Individuals with Proteus syndrome may also present with dysmorphic facial features, intellectual disability, seizures and/or brain malformations. Deep vein thrombosis (DVT) is also common.

The clinical sensitivity for Proteus syndrome is calculated based on the identification of a single known somatic mosaic pathogenic AKT1 variant in individuals meeting diagnostic criteria. The sensitivity for detecting a pathogenic variant derived from a blood specimen in an individual with Proteus syndrome is unknown; as Proteus syndrome is hypothesized to be lethal if present in the germline.

Proteus syndrome is caused by constitutionally mosaic pathogenic variants in AKT1.

The prevalence of Proteus syndrome is 1:1,000,000 – 1:10,000,000.

This test can be considered for individuals who meet clinical diagnostic criteria for Proteus syndrome (PMID: 23992099).

This test can be considered for individuals who meet clinical diagnostic criteria for Proteus syndrome (PMID: 23992099).

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
AKT1 NM_005163.2