Sorted By Test Name - Mayo Medical Laboratories

CDKKM
60229
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
CDKN1C Gene, Known Mutation
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. 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.
Useful For: 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
Interpretation: 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.
Reference Values:
An interpretive report will be provided.
Clinical References: 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
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