Test Catalog

Test Id : BWRS

Beckwith-Wiedemann Syndrome/Russell-Silver Syndrome, Molecular Analysis, Varies

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

Confirming a clinical diagnosis of Beckwith-Wiedemann syndrome (BWS) or Russell-Silver syndrome (RSS)

 

Prenatal diagnosis if there is a high suspicion of BWS/RSS based on ultrasound findings or in families at risk for BWS/RSS

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 deletions/duplications and determines methylation status in the BWS/RSS gene cluster.

 

Germline and prenatal testing are available on blood and amniocyte specimens, respectively. Prenatal testing for Beckwith-Wiedemann syndrome and Russell-Silver syndrome cannot be performed on chorionic villus specimens.

Reflex Tests
Lists tests that may or may not be performed, at an additional charge, depending on the result and interpretation of the initial tests.

Test Id Reporting Name Available Separately Always Performed
CULAF Amniotic Fluid Culture/Genetic Test Yes No
MATCC Maternal Cell Contamination, B Yes No
FIBR Fibroblast Culture Yes No
CRYOB Cryopreserve for Biochem Studies No No

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

For skin biopsy specimens only: If skin biopsy is received, fibroblast culture and cryopreservation for biochemical studies will be performed at an additional charge.

 

For prenatal specimens only:

If an amniotic fluid specimen is received, amniotic fluid culture will be performed at an additional charge.

For any prenatal specimen that is received, maternal cell contamination testing will be performed at an additional charge.

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

Method Name
A short description of the method used to perform the test

Methylation-Sensitive Multiplex Ligation-Dependent Probe Amplification (MLPA)

NY State Available
Indicates the status of NY State approval and if the test is orderable for NY State clients.

Yes

Reporting Name
Lists a shorter or abbreviated version of the Published Name for a test

BWS/RSS Molecular Analysis

Aliases
Lists additional common names for a test, as an aid in searching

Beckwith-Wiedemann Syndrome (BWS)

BWS (Beckwith-Wiedemann Syndrome)

BWSRS

H19

IC1

IC2

LIT1

RSS (Russell-Silver syndrome)

Russell-Silver syndrome (RSS)

Silver-Russell syndrome (SRS)

SRS (Silver-Russell syndrome)

Wilm's Tumor

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

For skin biopsy specimens only: If skin biopsy is received, fibroblast culture and cryopreservation for biochemical studies will be performed at an additional charge.

 

For prenatal specimens only:

If an amniotic fluid specimen is received, amniotic fluid culture will be performed at an additional charge.

For any prenatal specimen that is received, maternal cell contamination testing will be performed at an additional charge.

Specimen Type
Describes the specimen type validated for testing

Varies

Additional Testing Requirements

All prenatal specimens must be accompanied by a maternal blood specimen; order MATCC / Maternal Cell Contamination, Molecular Analysis, Varies on the maternal specimen as this must be a different order number than the prenatal specimen.

Shipping Instructions

Specimen preferred to arrive within 96 hours of collection.

Specimen Required
Defines the optimal specimen required to perform the test and the preferred volume to complete testing

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.

 

Submit only 1 of the following specimens:

 

Preferred:

Specimen Type: Blood

Container/Tube:

Preferred: Lavender top (EDTA) or yellow top (ACD)

Acceptable: Any anticoagulant

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send specimen in original tube.

Specimen Stability Information: Ambient (preferred)/Refrigerated/Frozen

 

Specimen Type: Cultured fibroblasts

Container/Tube: T-75 or T-25 flask

Specimen Volume: 1 Full T-75 or 2 full T-25 flasks

Specimen Stability Information: Ambient (preferred)/Refrigerated <24 hours

 

Due to the complexity of prenatal testing, consultation with the laboratory is required for all prenatal testing.

Specimen Type: Amniotic fluid

Container/Tube: Amniotic fluid container

Specimen Volume: 20 mL

Specimen Stability Information: Refrigerated (preferred)/Ambient

Additional information: A separate culture charge will be assessed under CULAF / Culture for Genetic Testing, Amniotic Fluid. An additional 2 to 3 weeks is required to culture amniotic fluid before genetic testing can occur.

 

Acceptable:

Specimen Type: Confluent cultured amniocytes

Container/Tube: T-25 flask

Specimen Volume: 2 flasks

Collection Instructions: Submit confluent cultured amniocytes from another laboratory.

Specimen Stability Information: Ambient (preferred)/Refrigerated

 

Specimen Type: Skin biopsy

Supplies: Fibroblast Biopsy Transport Media (T115)

Container/Tube: Sterile container with any standard cell culture media (eg, minimal essential media, RPMI 1640). The solution should be supplemented with 1% penicillin and streptomycin.

Specimen Volume: 4-mm punch

Specimen Stability Information: Refrigerated (preferred)/Ambient

Additional information: A separate culture charge will be assessed under FIBR / Fibroblast Culture, Tissue. An additional 4 weeks is required to culture fibroblasts before genetic testing can occur.

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

Forms

1. 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 in Special Instructions:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing-Spanish (T826)

2. Molecular Genetics: Congenital Inherited Diseases Patient Information (T521) in Special Instructions

Specimen Minimum Volume
Defines the amount of sample necessary to provide a clinically relevant result as determined by the Testing Laboratory

Blood: 1 mL

Amniotic Fluid: 10 mL

Reject Due To
Identifies specimen types and conditions that may cause the specimen to be rejected

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

Specimen Stability Information
Provides a description of the temperatures required to transport a specimen to the performing laboratory, alternate acceptable temperatures are also included

Specimen Type Temperature Time Special Container
Varies Varies (preferred)

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

Confirming a clinical diagnosis of Beckwith-Wiedemann syndrome (BWS) or Russell-Silver syndrome (RSS)

 

Prenatal diagnosis if there is a high suspicion of BWS/RSS based on ultrasound findings or in families at risk for BWS/RSS

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 deletions/duplications and determines methylation status in the BWS/RSS gene cluster.

 

Germline and prenatal testing are available on blood and amniocyte specimens, respectively. Prenatal testing for Beckwith-Wiedemann syndrome and Russell-Silver syndrome cannot be performed on chorionic villus specimens.

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

For skin biopsy specimens only: If skin biopsy is received, fibroblast culture and cryopreservation for biochemical studies will be performed at an additional charge.

 

For prenatal specimens only:

If an amniotic fluid specimen is received, amniotic fluid culture will be performed at an additional charge.

For any prenatal specimen that is received, maternal cell contamination testing will be performed at an additional charge.

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

Beckwith-Wiedemann syndrome (BWS) is a disorder characterized by prenatal and/or postnatal overgrowth, neonatal hypoglycemia, congenital malformations, and an increased risk for embryonal tumors. Physical findings are variable and can include abdominal wall defects, macroglossia, and hemihyperplasia. The predisposition for tumor development is associated with specific tumor types such as adrenal carcinoma, nephroblastoma (Wilms tumor), hepatoblastoma, and rhabdomyosarcoma. In infancy, BWS has a mortality rate of approximately 20%.

 

Current data suggest that the etiology of BWS is due to dysregulation of imprinted genes in the 11p15 region of chromosome 11, including H19 (maternally expressed), LIT1 (official symbol KCNQ1OT1; paternally expressed), IGF2 (paternally expressed), and CDKN1C (aliases p57 and KIP2; maternally expressed). Expression of these genes is controlled by 2 imprinting centers (IC).

 

Approximately 85% of BWS cases appear to be sporadic, while 15% of cases are associated with an autosomal dominant inheritance pattern. When a family history is present, the etiology is often due to inherited point alterations in CDKN1C or an unknown cause. The etiology of sporadic cases includes:

-Hypomethylation of imprinting center 2 (IC2) (LIT1): approximately 50% to 60%

-Paternal uniparental disomy of chromosome 11: approximately 10% to 20%

-Hypermethylation of imprinting center 1 (IC1) (H19): approximately 2% to 7%

-Unknown: approximately 10% to 20%

-Point alteration in CDKN1C: approximately 5% to 10%

-Cytogenetic abnormality: approximately 1% to 2%

-Differentially methylated region 1 (DMR1) or DMR2 microdeletion: rare

 

The clinical presentation of BWS is dependent on which gene in the 11p15 region is involved. The risk for cancer has been shown to be significantly higher in patients with abnormal methylation of IC1 (H19) versus IC2 (LIT1). In patients with abnormal methylation of IC2 (LIT1), abdominal wall defects and overgrowth are seen at a higher frequency.

 

Russell-Silver syndrome (RSS) is a rare genetic condition with an incidence of approximately 1 in 100,000. RSS is characterized by pre- and postnatal growth retardation with normal head circumference, characteristic facies, fifth finger clinodactyly, and asymmetry of the face, body, and/or limbs. Less commonly observed clinical features include cafe au lait spots, genitourinary anomalies, motor, speech, cognitive delays, and hypoglycemia. Although clinical diagnostic criteria have been developed, it has been demonstrated that many patients with molecularly confirmed RSS do not meet strict clinical diagnostic criteria for RSS. Therefore, most groups recommend a relatively low threshold for considering molecular testing in suspected cases of RSS.

 

RSS is a genetically heterogeneous condition that is associated with genetic and epigenetic alterations at chromosome 7 and the chromosome 11p15.5 region. The majority of cases of RSS are sporadic, although familial cases have been reported. The etiology of sporadic cases of RSS includes:

-Hypomethylation of IC1 (H19): approximately 30% to 50%

-Maternal uniparental disomy (UPD) of chromosome 7: approximately 5% to 10%*

-11p15.5 duplications: rare

-Chromosome 7 duplications: rare*

*Note that this test does not detect chromosome 7 UPD. However, testing is available; order UNIPD / Uniparental Disomy, Varies.

 

The clinical phenotype of RSS has been associated with the specific underlying molecular etiology. Patients with hypomethylation of IC1 (H19) are more likely to exhibit "classic" RSS phenotype (ie, severe intrauterine growth retardation, postnatal growth retardation, and asymmetry), while patients with maternal UPD7 often show a milder clinical phenotype. Despite these general genotype-phenotype correlations, many exceptions have been reported.

 

Methylation abnormalities of IC1 (H19) and IC2 (LIT1) can be detected by methylation-sensitive multiple ligation-dependent probe amplification. While testing can determine methylation status, it does not identify the mechanism responsible for the methylation defect (such as paternal uniparental disomy or cytogenetic abnormalities). Hypomethylation of IC2 (LIT1) is hypothesized to silence the expression of a number of maternally expressed genes, including CDKN1C. Hypermethylation of IC1 is hypothesized to silence the expression of H19, while also resulting in overexpression of IGF2. Absence of CDKN1C and H19 expression, in addition to overexpression of IGF2, is postulated to contribute to the clinical phenotype of BWS. Hypomethylation of IC1 is hypothesized to result in overexpression of H19 and underexpression of the IGF2, which is thought to contribute to the clinical phenotype of RSS.

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

An interpretive report will be provided.

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

In addition to disease-related probes, the multiple ligation-dependent probe amplification technique utilizes probes localized to other chromosomal regions as internal controls. In certain circumstances, these control probes may detect other diseases or conditions for which this test was not specifically intended. Results of the control probes are not normally reported. However, in cases where clinically relevant information is identified, the ordering physician will be informed of the result and provided with recommendations for any appropriate follow-up testing.

 

Rare alterations (ie, polymorphisms) exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.

 

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in the interpretation of results may occur if information given is inaccurate or incomplete.

 

Methylation status cannot be assessed on chorionic villus specimens.

 

This assay does not detect maternal uniparental disomy of chromosome 7 or cytogenetic abnormalities such as translocations, inversions, or duplications.

Supportive Data

Normal methylation index was derived by studying 150 normal individuals. For 65 patients referred for Beckwith-Wiedemann syndrome testing, results of this multiple ligation-dependent probe amplification (MLPA) assay were compared to a Southern blot method. Results were concordant for 64 of 65 specimens. In one specimen, a deletion was identified by MLPA that was not detected by the Southern blot method. For 55 patients referred for Russell-Silver syndrome testing, results of this MLPA assay were compared to H19 Southern blot. Results were concordant for 53 of 55 specimens. Two amniotic fluid specimens were positive for a H19 hypomethylation defect by Southern blot that were not detected by MLPA.

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

1. DeBaun MR, Niemitz EL, McNeil DE, Brandenburg SA, Lee MP, Feinberg AP: Epigenetic alterations of H19 and LIT1 distinguish patients with Beckwith-Wiedemann Syndrome with cancer and birth defects. Am J Hum Genet. 2002;70:604-611

2. Choufani S, Shuman C, Weksberg R: Beckwith-Wiedemann Syndrome. Am J Med Genet C Semin Med Genet. 2010 Aug 15;154C(3):343-354

3. Wakeling EL: Silver-Russell syndrome. Arch Dis Child. 2011 Dec;96(12):1156-1161

4. Eggermann T, Begemann M, Binder G, Spengler S: Silver-Russell syndrome: genetic basis and molecular genetic testing. Orphanet J Rare Dis. 2010 Jun 23;5:19-26

5. Priolo M, Sparago A, Mammi C, Cerrato F, Lagana C, Riccio A: MS-MLPA is a specific and sensitive technique for detecting all chromosome 11p15.5 imprinting defects of BWS and SRS in a single-tube experiment. Eur J Hum Genet. 2008 May;16(5):565-571

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

Method Description
Describes how the test is performed and provides a method-specific reference

Methylation-sensitive multiple ligation-dependent probe amplification is utilized to test for the presence of large deletions, duplications, and methylation defects in the imprinting center 1 (IC1) (H19) and IC2 (LIT1) critical regions on chromosome 11p15.(Unpublished Mayo method)

PDF Report
Indicates whether the report includes an additional document with charts, images or other enriched information

No

Day(s) Performed
Outlines the days the test is performed. This field reflects the day that the sample must be in the testing laboratory to begin the testing process and includes any specimen preparation and processing time before the test is performed. Some tests are listed as continuously performed, which means that assays are performed multiple times during the day.

Report Available
The interval of time (receipt of sample at Mayo Clinic Laboratories to results available) taking into account standard setup days and weekends. The first day is the time that it typically takes for a result to be available. The last day is the time it might take, accounting for any necessary repeated testing.

14 days to 6 weeks

Specimen Retention Time
Outlines the length of time after testing that a specimen is kept in the laboratory before it is discarded

Whole Blood: 2 weeks (if available); Extracted DNA: 3 months

Performing Laboratory Location
Indicates the location of the laboratory that performs the test

Rochester

Fees
Several factors determine the fee charged to perform a test. Contact your U.S. or International Regional Manager for information about establishing a fee schedule or to learn more about resources to optimize test selection.

  • Authorized users can sign in to Test Prices for detailed fee information.
  • Clients without access to Test Prices can contact Customer Service 24 hours a day, seven days a week.
  • Prospective clients should contact their Regional Manager. For assistance, contact Customer Service.

Test Classification
Provides information regarding the medical device classification for laboratory test kits and reagents. Tests may be classified as cleared or approved by the US Food and Drug Administration (FDA) and used per manufacturer instructions, or as products that do not undergo full FDA review and approval, and are then labeled as an Analyte Specific Reagent (ASR) product.

This test was developed, and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the US Food and Drug Administration.

CPT Code Information
Provides guidance in determining the appropriate Current Procedural Terminology (CPT) code(s) information for each test or profile. The listed CPT codes reflect Mayo Clinic Laboratories interpretation of CPT coding requirements. It is the responsibility of each laboratory to determine correct CPT codes to use for billing.

CPT codes are provided by the performing laboratory.

81401-H19 (imprinted maternally expressed transcript [non-protein coding]) (eg, Beckwith-Wiedemann syndrome), methylation analysis

81401-KCNQ1OT1 (KCNQ1 overlapping transcript 1 [non-protein coding]) (eg, Beckwith-Wiedemann syndrome) methylation analysis 

88233-Tissue culture, skin or solid tissue biopsy (if appropriate)

88240-Cryopreservation (if appropriate)

88235-Tissue culture for amniotic fluid (if appropriate)

81265-Comparative analysis using Short Tandem Repeat (STR) markers; patient and comparative specimen (eg, pre-transplant recipient and donor germline testing, post-transplant non-hematopoietic recipient germline [eg, buccal swab or other germline tissue sample] and donor testing, twin zygosity testing or maternal cell contamination of fetal cells (if appropriate)

Test Setup Resources

Setup Files
Test setup information contains test file definition details to support order and result interfacing between Mayo Clinic Laboratories and your Laboratory Information System.

Excel | Pdf

Sample Reports
Normal and Abnormal sample reports are provided as references for report appearance.

Normal Reports | Abnormal Reports

SI Sample Reports
International System (SI) of Unit reports are provided for a limited number of tests. These reports are intended for international account use and are only available through MayoLINK accounts that have been defined to receive them.

SI Normal Reports | SI Abnormal Reports