Test 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
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 |
FIBR | Fibroblast Culture | Yes | No |
CRYOB | Cryopreserve for Biochem Studies | No | No |
Testing Algorithm
If skin biopsy is received, fibroblast culture and cryopreservation for biochemical studies will be performed at an additional charge.
For prenatal specimens only: If amniotic fluid (nonconfluent cultured cells) is received, amniotic fluid culture/genetic test will be added at an additional charge. For any prenatal specimen that is received, maternal cell contamination studies will be added.
Special Instructions
Method Name
Methylation-Sensitive Multiplex Ligation-Dependent Probe Amplification (MLPA)
Reporting Name
BWS/RSS Molecular AnalysisSpecimen Type
VariesAdditional Testing Requirements
All prenatal specimens must be accompanied by a maternal blood specimen. Order MATCC / Maternal Cell Contamination, Molecular Analysis on the maternal specimen.
Shipping Instructions
Specimen preferred to arrive within 96 hours of collection.
Prenatal specimens can be sent Monday through Thursday and must be received by 5 p.m. Central on Friday in order to be processed appropriately.
Specimen Required
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
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
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
Specimen Minimum Volume
Blood: 1 mL/Amniotic Fluid: 10 mL
Specimen Stability Information
Specimen Type | Temperature | Time | Special Container |
---|---|---|---|
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.
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
An interpretive report will be provided.
Interpretation
An interpretive report will be provided.
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;70:604-611
2. Choufani S, Shuman C, Weksberg R: Beckwith-Wiedemann Syndrome. Am J Med Genet C Semin 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, Spengler S: Silver-Russell syndrome: genetic basis and molecular genetic testing. Orphanet J Rare Dis. 2010;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;16:565-571
Day(s) and Time(s) Performed
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 daysTest 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 analysisÂ
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 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