Test ID: CDKMS
CDKN1C Gene, Full Gene Analysis
NY State Approved 
Indicates the status of NY State approval and if the test is orderable for NY State clients.
Useful For Suggests clinical disorders or settings where the test may be helpful
Confirming a clinical diagnosis of Beckwith-Wiedemann syndrome
Confirming a clinical diagnosis of IMAGe syndrome
Genetics Test Information Provides information that may help with selection of the correct test or proper submission of the test request
Testing includes full gene sequencing of the CDKN1C gene
Reflex Tests Lists test(s) that may or may not be performed, at an additional charge, depending on the result and interpretation of the initial test(s)
| Test ID | Reporting Name | Available Separately | Always Performed |
|---|---|---|---|
| FBC | Fibroblast Culture for Genetic Test | Yes | No |
Testing Algorithm Delineates situation(s) when tests are added to the initial order. This includes reflex and additional tests.
If skin biopsy is received, fibroblast culture for genetic test will be added and charged separately.
Special Instructions and Forms Describes specimen collection and preparation information, test algorithms, and other information pertinent to test. Also includes pertinent information and consent forms to be used when requesting a particular test
Method Name A short description of the method used to perform the test
Polymerase Chain Reaction (PCR) Followed by DNA Sequence Analysis
(PCR is utilized pursuant to a license agreement with Roche Molecular Systems, Inc.)
Reporting Name A shorter/abbreviated version of the Published Name for a test; an abbreviated test name
Aliases Lists additional common names for a test, as an aid in searching
KIP2
BWS (Beckwith-Wiedemann syndrome)
IMAGe syndrome
Beckwith-Wiedemann syndrome (BWS).
Specimen Type Describes the specimen type needed for testing
Specimen Required Defines the optimal specimen. This field describes the type of specimen required to perform the test and the preferred volume to complete testing. The volume allows automated processing, fastest throughput and, when indicated, repeat or reflex testing.
Forms:
1. Molecular Genetics-Congenital Inherited Diseases Patient Information Sheet (Supply 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 (Supply T576) is available in Special Instructions.
Specimen must arrive within 96 hours of collection.
Submit only 1 of the following specimens:
Specimen Type: Whole 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
Specimen Type: Cultured fibroblasts
Container/Tube: T-75 or T-25 flask
Specimen Volume: 1 full T-75 flask or 2 full T-25 flasks
Specimen Stability Information: Ambient (preferred)/Refrigerated <24 hours
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 [Supply T115]).
Specimen Volume: 4-mm punch
Specimen Stability Information: Refrigerated (preferred)/Ambient
Specimen Minimum Volume Defines the amount of specimen required to perform an assay once, including instrument and container dead space. Submitting the minimum specimen volume makes it impossible to repeat the test or perform confirmatory or perform reflex testing. In some situations, a minimum specimen volume may result in a QNS (quantity not sufficient) result, requiring a second specimen to be collected.
Reject Due To Identifies specimen types and conditions that may cause the specimen to be rejected
| Hemolysis | NA |
| Lipemia | NA |
| Icterus | NA |
| Other | Plasma or serum |
Specimen Stability Information Provides a description of the temperatures required to transport a specimen to the laboratory. Alternate acceptable temperature(s) are also included.
| Specimen Type | Temperature | Time |
|---|---|---|
| Varies | Varies | |
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. Imprinting describes a difference in gene expression based on parent of origin. The majority of autosomal genes exhibit biallelic (maternal and paternal) expression, whereas imprinted genes normally express only 1 gene copy (either from the maternal or paternal allele). Imprinted genes are usually regulated by methylation, which prevents the gene from being expressed. Loss of expression or biallelic expression of an imprinted gene can lead to disease because of dosage imbalance. Some of the imprinted genes located in the region of 11p15 include H19 (maternally expressed), LIT1 (official symbol KCNQ1OT1; paternally expressed), IGF2 (paternally expressed), and CDKN1C (aliases p57 and KIP2; maternally expressed).
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 due to inherited point mutations in CDKN1C in approximately 40% of cases. The etiology of sporadic cases includes:
-Hypomethylation of LIT1: approximately 50% to 60%
-Paternal uniparental disomy of chromosome 11: approximately 10% to 20%
-Hypermethylation of 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 CDKN1C gene encodes a cyclin-dependent kinase inhibitor that acts as a negative regulator of cell proliferation and fetal growth. CDKN1C also functions as a tumor suppressor gene. Normally, CDKN1C is imprinted on the paternal allele and expressed only on the maternal allele. Absence of CDKN1C expression resulting from mutations of the maternally-inherited allele is postulated to contribute to the clinical phenotype of BWS.
The appropriate first-tier test in the evaluation of a possible diagnosis of BWS is BWSRS/61010 Beckwith-Wiedemann Syndrome (BWS)/Russell-Silver Syndrome (RSS) Molecular Analysis. CDKMS/60228 CDKN1C Gene, Full Gene Analysis should be ordered when results of BWS Methylation Analysis are negative and there is still a strong clinical suspicion of BWS.
Mutations in the CDKN1C gene have also been linked to IMAGe syndrome (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita and genital anomalies). The CDKN1C mutations associated with IMAGe syndrome tend to be missense mutations occurring in the PCNA-binding domain of the gene.
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
All detected alterations are evaluated according to American College of Medical Genetics and Genomics (ACMG) recommendations.(6) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
A small percentage of individuals who are carriers or have a diagnosis of Beckwith-Wiedemann syndrome or IMAGe syndrome caused by CDKN1C may have a mutation that is not identified by this method (eg, large genomic deletions, promoter mutations). The absence of a mutation, therefore, does not eliminate the possibility of positive carrier status or the diagnosis of Beckwith-Wiedemann syndrome or IMAGe syndrome. For carrier testing, it is important to first document the presence of a CDKN1C gene mutation in an affected family member.
In some cases, DNA alterations of undetermined significance may be identified.
Rare 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.
A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories at 1-800-533-1710 for instructions for testing patients who have received a bone marrow transplant.
Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.
Clinical Reference Provides recommendations for further in-depth reading of a clinical nature
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. Romanelli V, Belinchon A, Benito-Sanz S, et al: CDKN1C (p57[Kip2]) Analysis in Beckwith-Wiedemann Syndrome (BWS) Patients: Genotype-Phenotype Correlations, Novel Mutations, and Polymorphisms. Am J of Med Genet Part A 2010;152A:1390-1397
4. Lam WWK, Hatada I, Ohishi S, et al: Analysis of germline CDKNIC (p57[Kip2]) mutations in familial and sporadic Beckwith-Wiedemann syndrome (BWS) provides a novel genotype-phenotype correlation. J Med Genet 1999;36:518-523
5. Arboleda VA, Lee H, Parnaik R, et al: Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome. Nature Genetics 2012;44(7):788-792
6. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med 2008 Apr;10(4):294-300
Method Description Describes how the test is performed and provides a method-specific reference
DNA sequencing is utilized to test for the presence of a mutation in all coding regions and intron/exon boundaries of the CDKN1C gene (excluding c.481-c.595).(Unpublished Mayo method)
Day(s) and Time(s) Test Performed Outlines the days and times the test is performed. This field reflects the day and time the sample must be in the testing laboratory to begin the testing process and includes any specimen preparation and processing time required before the test is performed. Some tests are listed as continuously performed, which means assays are performed several times during the day.
Friday; 10 a.m.
Analytic Time Defines the amount of time it takes the laboratory to setup and perform the test. This is defined in number of days. The shortest interval of time expressed is "same day/1 day," which means the results may be available the same day that the sample is received in the testing laboratory. One day means results are available 1 day after the sample is received in the laboratory.
Maximum Laboratory Time Defines the maximum time from specimen receipt at Mayo Medical Laboratories until the release of the test result
Specimen Retention Time Outlines the length of time after testing that a specimen is kept in the laboratory before it is discarded
Performing Laboratory Location The location of the laboratory that performs the test
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's instructions, or as products that do not undergo full FDA review and approval, and are then labeled as an Analyte Specific Reagent (ASR), Investigation Use Only (IUO) product, or a Research Use Only (RUO) product.
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 Medical Laboratories interpretation of CPT coding requirements. It is the responsibility of each laboratory to determine correct CPT codes to use for billing.
81479-Unlisted molecular pathology procedure
LOINC® Code Information Provides guidance in determining the Logical Observation Identifiers Names and Codes (LOINC) values for the result codes returned for this test or profile.
| Result ID | Reporting Name | LOINC Code |
|---|---|---|
| 33492 | Specimen | N/A |
| 33493 | Specimen ID | N/A |
| 33494 | Source | N/A |
| 33495 | Order Date | N/A |
| 33496 | Reason for Referral | N/A |
| 33497 | Method | N/A |
| 33498 | Result | N/A |
| 33499 | Interpretation | N/A |
| 33500 | Amendment | N/A |
| 33501 | Reviewed By | N/A |
| 33502 | Release Date | N/A |
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