CDKN1C Gene, Known Mutation
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.
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.
Determining if a CDKN1C mutation identified in an affected individual is maternally inherited or de novo
Diagnostic confirmation of Beckwith-Wiedemann syndrome or IMAGe syndrome when a CDKN1C mutation has been identified in an affected family member
Carrier screening of at-risk individuals when a CDKN1C mutation has been identified in an affected family member
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
The identification of a disease-causing mutation in an affected family member is necessary before predictive testing for other family members can be offered. If a familial mutation has not been previously identified, order CDKMS / CDKN1C Gene, Full Gene Analysis.
Analysis is performed for the familial mutations provided only. This assay does not rule out the presence of other mutations within this gene or within other genes that may be associated with Beckwith-Wiedemann syndrome.
Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Any error in the diagnosis or in the pedigree provided to us, including false paternity, could lead to erroneous interpretation of results.
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.
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.
Clinical References 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