Test Code GNPRS Protein S Deficiency, PROS1 Gene, Next-Generation Sequencing, Varies

Ordering Guidance

This test should only be considered if clinical and family history, initial coagulation screens, and/or initial antigen and activity tests suggest a diagnosis of protein S deficiency (see Testing Algorithm).

This test does not measure protein S activity or antigen levels.

-For assessment of free protein S activity, order S_FX / Protein S Activity, Plasma.

-For assessment of plasma free protein S antigen, order PSTF / Protein S Antigen, Plasma.

For patients in whom hereditary protein S deficiency is strongly suspected and the plasma free protein S antigen level is normal, consider testing free protein S activity for detecting type II protein S deficiency, which is very rare. Order S_FX / Protein S Activity, Plasma.

If genetic testing for hereditary blood clotting disorders using a larger panel is desired, a 16-gene comprehensive thrombosis panel is available; order GNTHR / Thrombosis Disorders, Comprehensive Gene Panel, Next-Generation Sequencing, Varies.

Testing for the PROS1 gene as part of a customized panel is available. For more information see CGPH / Custom Gene Panel, Hereditary, Next-Generation Sequencing, Varies.

Targeted testing for familial variants (also called site-specific or known variants testing) is available for the PROS1 gene. See FMTT / Familial Variant, Targeted Testing, Varies. To obtain more information about this testing option, call 800-533-1710.

Shipping Instructions

Specimen preferred to arrive within 96 hours of collection.

Necessary Information

Rare Coagulation Disorder Patient Information is required. Testing may proceed without the patient information, however, the information aids in providing a more thorough interpretation. Ordering providers are strongly encouraged to fill out the form and send with the specimen.

Specimen Required

Specimen Type: Whole blood

Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. Call 800-533-1710 for instructions for testing patients who have received a bone marrow transplant.

Container/Tube:

Preferred: Lavender top (EDTA)

Acceptable: Yellow top (ACD)

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send whole blood specimen in original tube. Do not aliquot.

Specimen Stability Information: Ambient (preferred) 4 days/Refrigerated

Forms

1. Rare Coagulation Disorder Patient Information (T824) is required.

2. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing (Spanish) (T826)

3. If not ordering electronically, complete, print, and send an Coagulation Test Request (T753) with the specimen.

Secondary ID

619187

Useful For

Evaluating protein S deficiency in patients with a personal or family history suggestive of this hereditary thrombophilia

Confirming a diagnosis of autosomal dominant protein S deficiency with the identification of a known or suspected disease-causing alteration in the PROS1 gene

Confirming a diagnosis of autosomal recessive severe protein S deficiency with the identification of homozygous or compound heterozygous disease-causing alteration(s) in the PROS1 gene

Determining the disease-causing alteration(s) within the PROS1 gene to delineate the underlying molecular defect in a patient with a laboratory diagnosis of protein S deficiency

Prognosis and risk assessment based on the genotype-phenotype correlations

Ascertaining the variant status of family members related to an individual with a confirmed PROS1 variant for the purposes of informing clinical management and genetic counseling

Carrier testing for close family members of an individual with a diagnosis of autosomal recessive severe protein S deficiency

This test is not intended for prenatal diagnosis.

Testing Algorithm

The clinical workup for protein S deficiency should begin with measurement of plasma free protein S antigen.

Genetic testing for protein S deficiency is indicated if:

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

-There is a clinical suspicion of hereditary thrombophilia and possible protein S deficiency due to family history or atypical clinical presentation

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

Special Instructions

Method Name

Sequence Capture and Targeted Next-Generation Sequencing (NGS) followed by Polymerase Chain Reaction (PCR) and Sanger Sequencing

Reporting Name

PROS1 Gene, Full Gene NGS

Specimen Type

Varies

Specimen Minimum Volume

1 mL

Specimen Stability Information

Specimen Type	Temperature	Time	Special Container
Varies	Varies

Reject Due To

All specimens will be evaluated at Mayo Clinic Laboratories for test suitability.

Clinical Information

Hereditary protein S deficiency is a rare inherited clotting disorder (thrombophilia) associated with germline variants in the PROS1 gene. Protein S is an important component of the bodyâ€™s natural anticoagulant system. A deficiency results in an unchecked clotting cascade and increased risk of thromboembolism.(1)

Mild protein S deficiency is caused by heterozygous variants in one copy of PROS1 and is inherited in an autosomal dominant manner with incomplete penetrance. Individuals with mild protein S deficiency have a predisposition to developing venous thromboembolism, and often experience deep vein thrombosis and/or pulmonary embolism. Affected women have an increased risk for pregnancy loss and complications. The estimated prevalence is 0.16% to 0.21%.(1-4)

Severe protein S deficiency is caused by homozygous or compound heterozygous variants in PROS1 and is inherited in an autosomal recessive manner. It is quite rare and presents with neonatal purpura fulminans and disseminated intravascular coagulation.(1-3)

Causes of acquired (nongenetic) protein S deficiency should be excluded prior to genetic testing, including vitamin K deficiency, oral anticoagulant therapy, presence of liver disease, intravascular coagulation and fibrinolysis/disseminated intravascular coagulation, thrombotic thrombocytopenia purpura, pregnancy, and estrogen therapy. As an acute-phase reactant, plasma C4b-binding protein levels increase with acute illness and may cause acquired free protein S deficiency.(2)

The British Society for Haematology provides guidelines regarding diagnosis, management, and laboratory testing for individuals with hereditary thrombophilias including protein S deficiency.(5)

Reference Values

An interpretive report will be provided.

Interpretation

All detected variants are evaluated according to American College of Medical Genetics and Genomics recommendations.(7) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

Method Description

Next-generation sequencing (NGS) and/or Sanger sequencing are performed to test for the presence of variants in coding regions and intron/exon boundaries of the PROS1 gene, as well as some other regions that have known disease-causing variants. The human genome reference GRCh37/hg19 build was used for sequence read alignment. At least 99% of the bases are covered at a read depth over 30X. Sensitivity is estimated at above 99% for single nucleotide variants, above 94% for deletions-insertions (delins) less than 40 base pairs (bp), above 95% for deletions up to 75 bp, and insertions up to 47 bp. NGS and/or a polymerase chain reaction-based quantitative method is performed to test for the presence of deletions and duplications in the PROS1 gene.

There may be regions of the PROS1 gene that cannot be effectively evaluated by sequencing or deletion and duplication analysis as a result of technical limitations of the assay, including regions of homology, high guanine-cytosine (GC) content, and repetitive sequences.(Unpublished Mayo method)

The reference transcript for PROS1 is NM_000313.4. Reference transcript numbers may be updated due to transcript re-versioning. Always refer to the final patient report for gene transcript information referenced at the time of testing. Confirmation of select reportable variants may be performed by alternate methodologies based on internal laboratory criteria.

Day(s) Performed