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Test ID: BWRS Beckwith-Wiedemann Syndrome (BWS)/Russell-Silver Syndrome (RSS) Molecular Analysis

Useful For

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

Reflex Tests

Test ID Reporting Name Available Separately Always Performed
CULFB Fibroblast Culture for Genetic Test Yes No
CULAF Amniotic Fluid Culture/Genetic Test Yes No
MATCC Maternal Cell Contamination, B Yes No

Testing Algorithm

If skin biopsy is received, fibroblast culture for genetic test will be added and charged separately.

 

For prenatal specimens only: If amniotic fluid (nonconfluent cultured cells) is received, amniotic fluid culture/genetic test will be added and charged separately. For any prenatal specimen that is received, maternal cell contamination studies will be added.

Method Name

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

Reporting Name

BWS/RSS Molecular Analysis

Specimen Type

Varies


Shipping Instructions


Specimen preferred to arrive within 96 hours of draw.



Specimen Required


Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories 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. Prenatal specimens can be sent Monday through Thursday and must be received by 5 p.m. CST on Friday in order to be processed appropriately. All prenatal specimens must be accompanied by a maternal blood specimen. Order MATCC / Maternal Cell Contamination, Molecular Analysis on the maternal specimen.

 

Specimen Type: Amniotic fluid

Container/Tube: Amniotic fluid container

Specimen Volume: 20 mL

Specimen Stability Information: Refrigerated (preferred)/Ambient

           

Acceptable:

Specimen Type: Confluent cultured cells

Container/Tube: T-25 flask

Specimen Volume: 2 flasks

Collection Instructions: Submit confluent cultured cells from another laboratory.

Specimen Stability Information: Ambient (preferred)/Refrigerated

 

Specimen Type: Skin biopsy

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. Tubes can be supplied upon request (Eagle's minimum essential medium with 1% penicillin and streptomycin [T115]).

Specimen Volume: 4-mm punch

Specimen Stability Information: Refrigerated (preferred)/Ambient


Specimen Minimum Volume

Blood: 1 mL/Amniotic Fluid: 10 mL

Specimen Stability Information

Specimen Type Temperature Time
Varies Varies

Clinical Information

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 mutations 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 mutation 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.

 

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

An interpretive report will be provided.

Interpretation

An interpretive report will be provided.

Clinical Reference

1. DeBaun MR, Niemitz EL, McNeil DE, et al: Epigenetic alterations of H19 and LIT1 distinguish patients with Beckwith-Wiedemann Syndrome with cancer and birth defects. Hum Genet 2002;70:604-611          

2. Choufani S, Shuman C, Weksberg R: Beckwith-Wiedemann Syndrome. Am J of Med Genet 2010;154C:343-354

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

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

5. Priolo M, Sparago A, Mammi C, et al: 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;16:565-571

Day(s) and Time(s) Performed

Monday; 10 a.m.

                             

Specimens received Monday through Thursday will be run on the following Monday. Specimens received Friday through Sunday will be set up a week from the following Monday.

Analytic Time

14 days

Test Classification

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 U.S. Food and Drug Administration.

CPT Code Information

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  

 

Fibroblast Culture for Genetic Test

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

88240-Cryopreservation (if appropriate)

 

Amniotic Fluid Culture/Genetic Test

88235-Tissue culture for amniotic fluid (if appropriate)

88240-Cryopreservation (if appropriate)

 

Maternal Cell Contamination, B

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)

LOINC Code Information

Test ID Test Order Name Order LOINC Value
BWRS BWS/RSS Molecular Analysis In Process

 

Result ID Test Result Name Result LOINC Value
52845 Result Summary 50397-9
52846 Result 82939-0
52847 Interpretation 69047-9
52848 Reason for Referral 42349-1
52849 Specimen 31208-2
52850 Source 31208-2
52851 Released By No LOINC Needed

Forms

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

2. New York Clients-Informed consent is required. Please document on the request form or electronic order that a copy is on file. An Informed Consent for Genetic Testing (T576) is available in Special Instructions.

Mayo Medical Laboratories | Genetics and Pharmacogenomics Catalog Additional Information:

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