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HelpTest Code CDKZ CDKN1C Gene, Full Gene Analysis, Varies
Useful For
Confirming a clinical diagnosis of Beckwith-Wiedemann syndrome following a normal result on methylation analysis
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Confirming a clinical diagnosis of IMAGe (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies) syndrome
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Confirming a clinical diagnosis of Russell-Silver syndrome following a normal result on methylation analysis and uniparental disomy (UPD) 7 studies
Genetics Test Information
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
For prenatal specimens only:
-If amniotic fluid (nonconfluent cultured cells) is received, amniotic fluid culture will be added at an additional charge.
-If chorionic villus specimen (nonconfluent cultured cells) is received, fibroblast culture will be added at an additional charge.
For any prenatal specimen that is received, maternal cell contamination testing will be performed at an additional charge.
 For skin biopsy or cultured fibroblast specimens, fibroblast culture testing will be performed at an additional charge. If viable cells are not obtained, the client will be notified.
Special Instructions
Method Name
Polymerase Chain Reaction (PCR) followed by DNA Sequencing
Reporting Name
CDKN1C Gene, Full Gene AnalysisSpecimen Type
VariesOrdering Guidance
This test is for CDKN1C gene sequencing. For a full evaluation of a possible diagnosis of Beckwith-Wiedemann Syndrome, the recommended first-tier test is BWRS / Beckwith-Wiedemann Syndrome/Russell-Silver Syndrome, Molecular Analysis, 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
Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. For instructions for 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:
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 whole blood specimen in original tube. Do not aliquot.
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
Additional information: 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: 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. Tubes can be supplied upon request (Eagle's minimum essential medium 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 CULFB / Fibroblast Culture for Biochemical or Molecular Testing. An additional 3 to 4 weeks is required to culture fibroblasts before genetic testing can occur.
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: Refrigerated (preferred)/Ambient
Additional information:
1. 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.
2. 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: Chorionic villi
Container/Tube: 15-mL tube containing 15 mL of transport media
Specimen Volume: 20 mg
Specimen Stability Information: Refrigerated
Additional information:
1. A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing. An additional 2 to 3 weeks is required to culture chorionic villi before genetic testing can occur.
2. 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: 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
Additional Information: 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
Blood: 1 mL; Other specimen types: See Specimen Required
Specimen Stability Information
| Specimen Type | Temperature | Time | Special Container |
|---|---|---|---|
| Varies | Varies | ||
Reject Due To
All specimens will be evaluated at Mayo Clinic Laboratories for test suitability.Clinical Information
The CDKN1C gene is an imprinted gene that has been associated with Beckwith-Wiedemann syndrome (BWS), IMAGe (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies) syndrome, and Russell-Silver syndrome (RSS). 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 are normally expressed from only one parent. CDKN1C is typically expressed on the maternally inherited allele.
Beckwith-Wiedemann Syndrome:
Beckwith-Wiedemann syndrome 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%.
Most cases of BWS are caused by hypomethylation of LIT1, paternal uniparental disomy of chromosome 11, or hypermethylation of H19. Approximately 5% to 10% of sporadic BWS cases and approximately 40% of BWS cases with a positive family history are caused by CDKN1C variants. The appropriate first-tier test in the evaluation of a possible diagnosis of BWS is BWRS / Beckwith-Wiedemann Syndrome/Russell-Silver Syndrome, Molecular Analysis, Varies. This test may be considered when the results of BWS methylation analysis are negative, and there is still a strong clinical suspicion of BWS.
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IMAGe Syndrome:
Variants in the CDKN1C gene have also been associated with IMAGe syndrome. The CDKN1C variants associated with IMAGe syndrome tend to be missense variants occurring in the PCNA-binding domain of the gene. Not every individual with a clinical diagnosis of IMAGe syndrome will have an identifiable CDKN1C variant.
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Russell-Silver Syndrome:
Russell-Silver syndrome is a rare genetic condition with an incidence of approximately 1 in 100,000. RSS is characterized by pre- and postnatal growth delay 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.
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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), maternal uniparental disomy (UPD) of chromosome 7, 11p15.5 duplications (rare), and chromosome 7 duplications (rare).
CDKN1C variants have recently been identified as a cause of RSS in some families. This test may be considered when results of RSS methylation analysis and UPD 7 studies are negative and there is still a strong clinical suspicion of RSS
Reference Values
An interpretive report will be provided.
Interpretation
All detected alterations are evaluated according to American College of Medical Genetics and Genomics recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.
Cautions
A small percentage of individuals who are carriers or have a diagnosis of Beckwith-Wiedemann syndrome, IMAGe (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita and genital anomalies) syndrome, or Russell-Silver syndrome caused by CDKN1C may have a variant that is not identified by this method (eg, large genomic deletions, promoter variants). The absence of a variant, therefore, does not eliminate the possibility of positive carrier status or the diagnosis of Beckwith-Wiedemann syndrome, IMAGe syndrome, or Russell-Silver syndrome. For carrier testing, it is important to first document the presence of a CDKN1C gene variant in an affected family member.
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In some cases, DNA alterations of undetermined significance may be identified.
Rare variants (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.
Clinical Reference
1. Richards S, Aziz N, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-424
2. 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 Mar;70(3):604-611
3. Choufani S, Shuman C, Weksberg R: Beckwith-Wiedemann syndrome. Am J Med Genet. 2010 Aug;154C(3):343-354
4. 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 Med Genet A. 2010 Jun;152A:1390-1397. doi: 10.1002/ajmg.a.33453
5. 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 Jul;36(7):518-523
6. Arboleda VA, Lee H, Parnaik R, et al: Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome. Nat Genet. 2012 May;44(7):788-792
Method Description
Bidirectional sequence analysis is performed to test for the presence of a variant in all coding regions and intron/exon boundaries of the CDKN1C gene (excluding c.481-c.595).(Unpublished Mayo method)
Day(s) Performed
Report Available
14 to 20 daysSpecimen Retention Time
Whole blood: 2 weeks (if available); Extracted DNA: 3 months; Cultured fibroblasts, skin biopsy, amniotic fluid, cultured amniocytes, chorionic villi, cultured chorionic villi: 1 monthPerforming Laboratory
Mayo Clinic Laboratories in Rochester
Test 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
81479
88233-Tissue culture, skin or solid tissue biopsy (if appropriate)
88240-Cryopreservation (if appropriate)
88235-Amniotic fluid culture (if appropriate)
81265-Maternal cell contamination (if appropriate)
LOINC Code Information
| Test ID | Test Order Name | Order LOINC Value |
|---|---|---|
| CDKZ | CDKN1C Gene, Full Gene Analysis | 94193-0 |
| Result ID | Test Result Name | Result LOINC Value |
|---|---|---|
| 53880 | Result Summary | 50397-9 |
| 53881 | Result | 82939-0 |
| 53882 | Interpretation | 69047-9 |
| 53883 | Additional Information | 48767-8 |
| 53884 | Specimen | 31208-2 |
| 53885 | Source | 31208-2 |
| 53886 | Released By | 18771-6 |
Secondary ID
35385Forms
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)