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Test Catalog

Test ID: PRSNG    
Protein S Deficiency, PROS1 Gene, Next-Generation Sequencing, Varies

Useful For Suggests clinical disorders or settings where the test may be helpful

Ascertaining a pathogenic alteration in the PROS1 gene of patient with congenital protein S deficiency

 

This test is not intended for prenatal diagnosis

Genetics Test Information Provides information that may help with selection of the correct genetic test or proper submission of the test request

This test detects pathogenic alterations in the PROS1 gene to delineate the underlying molecular defect in a patient with a laboratory diagnosis of thrombophilia due to protein S deficiency.

 

The gene target for this test is:

Gene name (transcript): PROS1 (GRCh37 [hg19] NM_000313)

Chromosomal location: 3q11.1

Testing Algorithm Delineates situations when tests are added to the initial order. This includes reflex and additional tests.

At Mayo Clinic, measurement of plasma free protein S antigen (PSTF / Protein S Antigen, Plasma) is performed as the initial testing for protein S deficiency. If the free protein S antigen is abnormal, then the total plasma protein S antigen will be performed to distinguish between types I and III protein S deficiency. For patients in whom hereditary protein S deficiency is strongly suspected and the free plasma protein S antigen level is normal, consideration should be given to testing of free protein S activity, S_FX / Protein S Activity, Plasma, for detecting type II protein S deficiency.

 

Genetic testing for protein S deficiency is indicated if:

- Free protein S antigen and/or activity is abnormally reduced

- Preanalytical variables and acquired causes of protein S deficiency have been excluded (eg, acute thrombosis, surgery, disseminated intravascular coagulation [DIC], liver disease, vitamin K deficiency, therapy with vitamin K antagonists such as warfarin, pregnancy, treatment with hormonal contraceptives, HIV infection, varicella, sickle cell disease, malignancy, nephrotic syndrome)

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Protein S (PS) is a vitamin K-dependent glycoprotein that is synthesized mainly in the liver and endothelium and is part of the natural anticoagulant system. It is a cofactor in the inactivation of procoagulant factors V and VIII. Most (60%) of protein S circulates in plasma in a form bound to C4b binding protein and the rest circulates freely and is termed "free PS". The free form serves as a cofactor to anticoagulant enzyme activated protein C (APC) in the proteolytic inactivation of procoagulant factors Va and VIIIa.

 

A congenital deficiency of protein S deficiency increases thrombotic risk by 8-10 fold compared to normal individuals. Nearly half of PS type I deficiency patients present with venous thromboembolism (VTE) until the age of 55; about half of these VTE events are unprovoked (1). The use of oral contraceptives in women deficient in protein S may increase the risk of VTE by 600-fold compared to individuals with normal PS levels. Women with PS deficiency also have a 3-fold increased risk for pregnancy loss and pregnancy complications (1). The prevalence of congenital protein S deficiency in the general population is 0.16% to 0.21%. The prevalence of protein S deficiency in patients with VTE is estimated to be 2% (2).

 

Congenital protein S deficiency is classified into three disease states. In type I PS deficiency, there is a decreased amount of both bound and free forms of protein S. In type II deficiency,protein function is altered but levels of protein S are normal. In type III deficiency, there is a low level of free protein S but a normal amount of total protein S. No differences in clinical presentation and severity have been observed for the different phenotypes.

 

The PROS1 gene encodes for protein S (PS). Alterations in PROS1 can lead to sustained activation of factors V and VIII and the continued production of thrombin, leading to an increased risk for thrombosis. Congenital protein S deficiency is inherited in an autosomal dominant manner with incomplete penetrance. Heterozygotes for a pathogenic alteration in PROS1 typically present with plasma protein S levels in the 35% to 60% range (3). Individuals who are homozygous or compound heterozygous for pathogenic alterations in PROS1 present with massive VTE or neonatal purpura fulminans, which is life-threatening if untreated. Retinopathy has also been observed as the presenting symptoms in some cases. Genetic testing of the PROS1 gene is indicated if free protein S antigen or activity is abnormally reduced and acquired causes of protein S deficiency have been excluded. Normal, full-term newborn infants or healthy premature infants may have decreased levels of total protein S (15%-50%); but because of low levels of C4bBP, free protein S may be normal or near the normal adult level (greater than or equal to 50%). Total protein S reaches adult levels by 90 to 180 days postnatal.

 

Acquired (non-genetic causes) of protein S deficiency are much more common than hereditary protein S deficiency. It is unknown if acquired deficiency of protein S results in increased thrombotic risk. Vitamin K deficiency, oral anticoagulant therapy, presence of liver disease, or intravascular coagulation and fibrinolysis/ disseminated intravascular coagulation (ICF/DIC), thrombotic thrombocytopenia purpura (TTP), pregnancy or estrogen therapy, and nephritic syndrome are common acquired causes of protein S deficiency. As an acute-phase reactant, plasma C4bBP levels increase with acute illness and may cause acquired free protein S deficiency. Additionally, many preanalytic factors may interfere with measurements of free and total protein S, such as the use of heparin, having hemoglobin levels greater than 20 g/dL, bilirubin (greater than 25 mg/dL for free protein S, greater than 100 mg/L for total protein S), or rheumatoid factor greater than 900 IU/mL. Free protein S measurements are affected by additional factors such as elevated triglycerides (greater than1,500 mg/dL), sickle cell anemia, and the presence of the factor V Leiden alteration in the F5 gene.

 

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided

Interpretation Provides information to assist in interpretation of the test results

Evaluation and categorization of variants is performed using the most recent published American College of Medical Genetics and Genomics recommendations as a guideline. Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

 

Consultations with the Mayo Clinic Special Coagulation Clinic, Molecular Hematopathology Laboratory, and Thrombophilia Center are available for DNA diagnosis cases. This may be especially helpful in complex cases or in situations where the diagnosis is atypical or uncertain.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Clinical:

Some individuals may have a mutation that is not identified by the methods performed. The absence of a mutation, therefore, does not eliminate the possibility of protein S deficiency. This assay does not distinguish between germline and somatic alterations, particularly with variant allele frequencies (VAF) significantly lower than 50%. Test results should be interpreted in context of clinical findings, family history, and other laboratory data. Misinterpretation of results may occur if the information provided is inaccurate or incomplete.

 

If there is a family history of protein S deficiency, it is often useful to test first-degree family members to help establish the clinical significance of variants of unknown significance.

 

Technical Limitations:

Next-generation sequencing (NGS) may not detect all types of genetic variants. Additionally, rare polymorphisms may be present that could lead to false-negative or false-positive results. Therefore test results should be interpreted in the context of activity and antigen measurements, clinical findings, family history, and other laboratory data. If results do not match clinical findings, consider alternative methods for analyzing these genes, such as Sanger sequencing or large deletion/duplication analysis. Misinterpretation of results may occur if the information provided is inaccurate or incomplete.

 

If multiple alterations are identified, NGS is not able to distinguish between alterations that are found in the same allele (in cis) and alterations found on different alleles (in trans). This limitation may complicate diagnosis or classification and has implications for inheritance and genetic counseling. To resolve these cases, molecular results must be correlated with clinical history, activity and antigen measurements, and family studies.

 

Unless reported or predicted to cause disease, alterations found deep in the intron or alterations that do not result in an amino acid substitution are not reported. These and common polymorphisms identified for this patient are available upon request.

 

Reclassification of Variants Policy:

At this time, it is not standard practice for the laboratory to systematically review likely pathogenic variants or variants of uncertain significance that are detected and reported. The laboratory encourages health care providers to contact the laboratory at any time to learn how the status of a particular variant may have changed over time.

 

Contact the laboratory if additional information is required regarding the transcript and/or human genome assembly used for the analysis of this patient's results.

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Brouwer JL, Veeger NJ, van der Schaaf W, et al: Difference in absolute risk of venous and arterial thrombosis between familial protein S deficiency type I and type III. Results from a family cohort study to assess the clinical impact of a laboratory test-based classification. Br J Haematol 2005;128:703-710

2. ten Kate MK, van der Meer J: Protein S deficiency: a clinical perspective. Haemophilia 2008;14:1222-1228

3. Marlar RA, Gausman JN: Protein S abnormalities: a diagnostic nightmare. Am J Hematol 2011;86:418-421

4. Duebgen S, Kauke T, Marschall C, et al: Genotype and laboratory and clinical phenotypes of protein S deficiency. Am J Clin Pathol 2012;137:178-184

5. Garcia de Frutos P, Fuentes-Prior P, Hurtado B, Sala N: Molecular basis of protein S deficiency. Thromb Haemost 2007;98:543-556

Special Instructions Library of PDFs including pertinent information and forms related to the test