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Test ID: CDKZ CDKN1C Gene, Full Gene Analysis, Varies

Reporting Name

CDKN1C Gene, Full Gene Analysis

Useful For

Confirming a clinical diagnosis of Beckwith-Wiedemann syndrome


Confirming a clinical diagnosis of intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita and genital anomalies (IMAGe) syndrome

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. 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 BWRS / Beckwith-Wiedemann Syndrome (BWS)/Russell-Silver Syndrome (RSS) Molecular Analysis. CDKZ / 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.


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.

Testing Algorithm

If skin biopsy is received, fibroblast culture for genetic test will be added and charged separately.

Reflex Tests

Test ID Reporting Name Available Separately Always Performed
CULFB Fibroblast Culture for Genetic Test Yes No

Analytic Time

14 days

Day(s) and Time(s) Performed

Performed weekly, Varies

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, 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

3. Choufani S, Shuman C, Weksberg R: Beckwith-Wiedemann Syndrome. Am J of 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 of Med Genet Part 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. Nature Genetics 2012;44(7):788-792

Method Name

Polymerase Chain Reaction (PCR) Followed by DNA Sequence Analysis

Specimen Type


Shipping Instructions

Specimen preferred to arrive within 96 hours of draw.

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


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 [T115]).

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

Reference Values

An interpretive report will be provided.

Test 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

81479-Unlisted molecular pathology procedure


Fibroblast Culture for Genetic Test

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


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

Mayo Clinic Laboratories | Endocrinology Catalog Additional Information: