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HelpTest ID: BWRS Beckwith-Wiedemann Syndrome/Russell-Silver Syndrome, Molecular Analysis, Varies
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
This assay does not detect maternal uniparental disomy of chromosome 7 or cytogenetic abnormalities such as translocations or inversions.
Reflex Tests
| Test ID | Reporting Name | Available Separately | Always Performed |
|---|---|---|---|
| CULAF | Amniotic Fluid Culture/Genetic Test | Yes | No |
| MATCC | Maternal Cell Contamination, B | Yes | No |
| CULFB | Fibroblast Culture for Genetic Test | Yes | No |
Testing Algorithm
For information see Beckwith-Wiedemann and Russell-Silver Syndromes: Laboratory Approach to Diagnosis
Special Instructions
Method Name
Multiplex Ligation-Dependent Probe Amplification (MLPA)
Reporting Name
BWS/RSS Molecular AnalysisSpecimen Type
VariesAdditional Testing Requirements
Shipping Instructions
Specimen preferred to arrive within 96 hours of collection.
Specimen Required
Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. For information about testing patients who have received a bone marrow transplant, call 800-533-1710.
Submit only 1 of the following specimens:
Specimen Type: Whole blood
Container/Tube: Lavender top (EDTA) or 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 4 days/Frozen 4 days
Additional Information:
1. Specimens are preferred to be received within 4 days of collection. Extraction will be attempted for specimens received after 4 days, and DNA yield will be evaluated to determine if testing may proceed.
2. To ensure minimum volume and concentration of DNA is met, the requested volume must be submitted. Testing may be canceled if DNA requirements are inadequate.
Specimen Type: Cord blood
Container/Tube: Lavender top (EDTA) or yellow top (ACD)
Specimen Volume: 3 mL
Collection Instructions:
1. Invert several times to mix blood.
2. Send specimen in original tube. Do not aliquot.
Specimen Stability Information: Ambient (preferred) 4 days/Refrigerated 4 days/Frozen 4 days
Additional Information:
1. Specimens are preferred to be received within 4 days of collection. Extraction will be attempted for specimens received after 4 days, and DNA yield will be evaluated to determine if testing may proceed.
2. To ensure minimum volume and concentration of DNA is met, the requested volume must be submitted. Testing may be canceled if DNA requirements are inadequate.
3. While a properly collected cord blood sample may not be at risk for maternal cell contamination, unanticipated complications may occur during collection.
Therefore, maternal cell contamination studies are recommended to ensure the test results reflect that of the patient tested and are available at an additional charge.
4. Order MATCC / Maternal Cell Contamination, Molecular Analysis, Varies on the maternal specimen.
Specimen Type: Cultured fibroblasts
Source: Skin
Container/Tube: T-25 flask
Specimen Volume: 2 Flasks
Collection Instructions: Submit confluent cultured fibroblast cells from a skin biopsy.
Specimen Stability Information: Ambient (preferred) <24 hours/Refrigerated <24 hours
Additional Information:
1. Specimens are preferred to be received within 24 hours of collection. Culture and/or extraction will be attempted for specimens received after 24 hours and will be evaluated to determine if testing may proceed.
2. A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing. An additional 3 to 4 weeks is required to culture fibroblasts before genetic testing can occur.
Specimen Type: Tissue biopsy
Supplies: Hank's Solution (T132)
Container/Tube: Sterile container with sterile Hank's balanced salt solution, Ringer's solution, or normal saline
Specimen Volume: 0.5 to 3 cm(3) or larger
Specimen Stability Information: Ambient (preferred) <24 hours/Refrigerated <24 hours
Additional Information:
1. Specimens are preferred to be received within 24 hours of collection. Culture and extraction will be attempted for specimens received after 24 hours and will be evaluated to determine if testing may proceed.
2. A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing. An additional 3 to 4 weeks is required to culture fibroblasts before genetic testing can occur.
Specimen Type: Extracted DNA
Container/Tube:
Preferred: Screw Cap Micro Tube, 2mL with skirted conical base
Acceptable: Matrix tube, 1mL
Collection Instructions:
1. The preferred volume is at least 100 mcL at a concentration of 75 ng/mcL.
2. Include concentration and volume on tube.
Specimen Stability Information: Frozen (preferred) 1 year/Ambient/Refrigerated
Additional Information: DNA must be extracted in a CLIA-certified laboratory or equivalent and must be extracted from a specimen type listed as acceptable for this test (including applicable anticoagulants). Our laboratory has experience with Chemagic, Puregene, Autopure, MagnaPure, and EZ1 extraction platforms and cannot guarantee that all extraction methods are compatible with this test. If testing fails, one repeat will be attempted, and if unsuccessful, the test will be reported as failed and a charge will be applied. If applicable, specific gene regions that were unable to be interrogated due to DNA quality will be noted in the report.
Prenatal Specimens
Due to its complexity, consultation with the laboratory is required for all prenatal testing; call 800-533-1710 to speak to a genetic counselor.
Specimen Type: Amniotic fluid
Container/Tube: Amniotic fluid container
Specimen Volume: 20 mL
Specimen Stability Information: Ambient (preferred) <24 hours/Refrigerated <24 hours
Additional Information: Specimen can be tested only after culture.
1. Specimens are preferred to be received within 24 hours of collection. Culture and extraction will be attempted for specimens received after 24 hours and will be evaluated to determine if testing may proceed.
2. 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.
3. All prenatal specimens must be accompanied by a maternal blood specimen; order MATCC / Maternal Cell Contamination, Molecular Analysis, Varies on the maternal specimen.
Specimen Type: Prenatal cultured amniocytes. This does not include cultured chorionic villi.
Container/Tube: T-25 flask
Specimen Volume: 2 Flasks
Collection Instructions: Submit confluent cultured cells from another laboratory.
Specimen Stability Information: Ambient (preferred) <24 hours/Refrigerated <24 hours
Additional Information:
1. Specimens are preferred to be received within 24 hours of collection. Culture and extraction will be attempted for specimens received after 24 hours and will be evaluated to determine if testing may proceed.
2. A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing.
3. All prenatal specimens must be accompanied by a maternal blood specimen; order MATCC / Maternal Cell Contamination, Molecular Analysis, Varies on the maternal specimen.
Specimen Minimum Volume
See Specimen Required
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 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.
Russell-Silver syndrome 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
An interpretive report will be provided.
Interpretation
The interpretive report includes an overview of the findings as well as the associated clinical significance.
Clinical Reference
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(3):604-611
2. Choufani S, Shuman C, Weksberg R. Beckwith-Wiedemann Syndrome. Am J Med Genet C Semin Med Genet. 2010;154C(3):343-354
3. Wakeling EL. Silver-Russell syndrome. Arch Dis Child. 2011;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;5:19
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;16(5):565-571
6. Brioude F, Kalish JM, Mussa A, et al. Expert consensus document: Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement. Nat Rev Endocrinol. 2018;14(4):229-249. doi:10.1038/nrendo.2017.166
7. Wakeling EL, Brioude F, Lokulo-Sodipe O, et al. Diagnosis and management of Silver-Russell syndrome: first international consensus statement. Nat Rev Endocrinol. 2017;13(2):105-124. doi:10.1038/nrendo.2016.138
Day(s) Performed
Varies
Report Available
10 to 14 daysTest Classification
This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. It has not been cleared or approved by the US 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
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)
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 | 18771-6 |
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:
-Informed Consent for Genetic Testing (T576)
-Informed Consent for Genetic Testing-Spanish (T826)
2. Molecular Genetics: Congenital Inherited Diseases Patient Information (T521)