Test ID: 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 intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies (IMAGe) 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.
Reflex Tests
Test ID | Reporting Name | Available Separately | Always Performed |
---|---|---|---|
FIBR | Fibroblast Culture | Yes | No |
CRYOB | Cryopreserve for Biochem Studies | No | No |
Testing Algorithm
If skin biopsy is received, fibroblast culture for genetic test will be added and charged separately.
Special Instructions
Method Name
Polymerase Chain Reaction (PCR) followed by DNA Sequencing
Reporting Name
CDKN1C Gene, Full Gene AnalysisSpecimen Type
VariesShipping 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. Call 800-533-1710 for instructions for testing patients who have received a bone marrow transplant.
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
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
Specimen Minimum Volume
Blood: 1 mL
Specimen Stability Information
Specimen Type | Temperature | Time | Special Container |
---|---|---|---|
Varies | Varies |
Clinical Information
The CDKN1C gene is an imprinted gene that has been associated with Beckwith-Wiedemann syndrome (BWS), intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies (IMAGe) 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.
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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%.
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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Intrauterine Growth Restriction, Metaphyseal Dysplasia, Adrenal Hypoplasia Congenita, and Genital Anomalies 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:
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.
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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 (ACMG) recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.
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;70:604-611
3. Choufani S, Shuman C, Weksberg R: Beckwith-Wiedemann Syndrome. Am J Med Genet. 2010;154C: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;152A:1390-1397
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;36:518-523
6. Arboleda VA, Lee H, Parnaik R, et al: Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome. Nat Genet. 2012;44(7):788-792
Day(s) Performed
Report Available
14 to 20 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 US Food and Drug Administration.CPT Code Information
81479
88233-Tissue culture, skin or solid tissue biopsy (if appropriate)
88240-Cryopreservation (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 |
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