ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000011.9) (NC_000011.10)
Evidence for haploinsufficiency phenotype
PubMed ID Description
20503313 Romanelli et al (2010) reported 8 sequence variants in CDKNC1 - one was a de novo frameshift variant and 4 others were maternally inherited loss-of-function variants in patients with BWS. In addition, this manuscript provides a review of other variants described in previous studies.
23197429 Kantaputra et al (2013) reported a novel variant in CDKN1C (c.579delT; p.A193AfsX46) found in all three affected sibs with BWS and their mother. This variant was not detected in 100 normal controls and in more than 12,000 exomes at the Exome Variant Server (
26077438 Brioude et at (2015) identified 37 heterozygous variants in 38 families (50 patients and 7 fetuses). The spectrum of the variants: 4 missense, 9 nonsense, 2 out of frame , 20 frameshift , and 2 splice site. Five out of these 37 variants (c.125T>C, c.176C>T, c.688C>T,c.812C>A, and c.812C>G) were recurrent variants, which have already been reported in BWS patients. Therefore, the authors identified 32 novel CDKN1C variants. Analysis of parental samples when available showed that all variants tested but one was inherited from the mother.

Haploinsufficiency phenotype comments:

Cyclin-dependent kinase (CDK)-inhibitor 1C (CDKN1C) (also known as p57KIP2) maps centromeric to the 11p15 region (IC2) and is a paternally imprinted and maternally expressed tumor suppressor gene. CDKN1C negatively regulates cellular proliferation. Maternally inherited loss of function variants in this gene have been implicated in 8% of Beckwith-Wiedemann syndrome (BWS) cases, including both sporadic (5-8%) and familial (40-50%) forms. Further, loss of Cdkn1c in mice exhibits a phenotype that closely resembles BWS. This congenital overgrowth syndrome is phenotypically variable and genotypically heterogeneous, characterized by macroglossia, abdominal wall defects, neonatal hypoglycemia, lateralized overgrowth and predisposition to embryonal tumors. In contrast, gain-of-function variants of the PCNA domain of CDKN1C are observed in individuals with IMAGe syndrome, a postnatal growth deficiency syndrome. BWS patients with variants in CDKN1C nearly always show abdominal wall defects (i.e., exomphalos or at least umbilical hernia) and seem to more often present with cleft palate, genital abnormalities, polydactyly, and extra nipples than BWS patients with other molecular defects. Patients with defects of IC2 and those with variants in CDKN1C have been reported to have a much lower risk of developing childhood tumors than do other patients with BWS. Smaller deletions within ICR2 require careful characterization. In cases of smaller deletions in 11p15.5 that affect CDKN1C itself and/or regulatory elements (e.g., enhancers), the extent and the parent of origin of the affected fragment has to be precisely determined, as both clinically affected and unaffected individuals have been reported, and prediction of the clinical outcome might be difficult. In general, three types of variant can be distinguished: (i) loss-of-function CDKN1C point variants that are associated with BWS; (ii) gain-of-function CDKN1C missense variants that cause growth-retardation syndromes such as IMAGe (currently these have been detected only in the PCNA-binding domain); and (iii) large alterations (such as deletions, duplications, and UPDs) in 11p15.5, the effect of which on the expression of CDKN1C depends on their size and genomic content. Therefore, two molecular properties of 11p15.5 must be considered to delineate the functional consequence of genomic imbalance: (i) the parent of origin; and (ii) the size of the deletion/ duplication. Additional publications: PMID: 31804259: Jurkiewicz et al (2020) identified three sporadic BWS patients with novel pathogenic variants in CDKN1C, including one missense (c.181T>C) and two frameshift (c.415_416dup, c.804delC). PMID: 19843502: Zollino et al (2010) reported a de novo 900 kb deletion of 11p15.5, including CDKN1C and 15 other genes, in a patient with BWS. The deletion was demonstrated to be maternal in origin by SNP array. PMID: 25262539: Eggermann et al (2014) 'CDKN1C mutations: two sides of the same coin' (Review Article).

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity
Evidence for triplosensitivity phenotype
PubMed ID Description
26358311 Xue et al (2015) described a paternal duplication of the 11p15 centromeric imprinting control region which was associated with increased expression of CDKN1C in a child with Silver?Russell syndrome (SRS). The microduplication was discontiguous, with a 34 kb and a 237 kb duplications separated by a 3.3 kb region with normal copy number. Genes located within the duplication include portions of KCNQ1 and KCNQ1OT1 and the entire CDKN1C, SLC22A18, SLC22A18AS, and PHLDA2. Normally paternally inherited CDKN1C is not expressed but the microduplication of paternal origin in this patient appeared to lead to increased expression of CDKN1C. The authors suggested that the expression of CDKN1C in the patient was not regulated by the methylation of IC2. A plausible explanation was that the duplication resulted in an aberrant KCNQ1OT1 transcript that was unstable.

Triplosensitivity phenotype comment:

Large paternally inherited duplications of 11p15.5, affecting both ICR1 and ICR2, are generally associated BWS. However, paternal duplications of only the centromeric imprinting cluster (IC2) are rare, and do not always include the CDKN1C gene. An isolated duplication of entire CDKN1C has not yet been reported.