Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders

Gene: CDKN1C

Green List (high evidence)

CDKN1C (cyclin dependent kinase inhibitor 1C)
EnsemblGeneIds (GRCh38): ENSG00000129757
EnsemblGeneIds (GRCh37): ENSG00000129757
OMIM: 600856, Gene2Phenotype
CDKN1C is in 20 panels

4 reviews

Helen Brittain (Genomics England Curator)

Green List (high evidence)

Although methylation is important in this condition, a subset of patients will have BWS as a result of a CDKN1C point mutation. Therefore, this gene should be green and tiering would be expected to pick up the mutation related cases.
Created: 25 May 2017, 1:47 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)

Phenotypes
Beckwith-Wiedemann syndrome 130650

Publications

Louise Daugherty (Genomics England Curator)

Green List (high evidence)

Review and Green rating from Kate Tatton-Brown April 2017: Note the mutations that cause Beckwith are different from the clustered CDKN1C mutations that cause IMAGe syndrome
Created: 31 May 2019, 9:20 a.m.
Should be noted that CDKN1C is ab example of allelic heterogeneity associated with opposite syndromes. Loss of function mutations in the maternal CDKN1C gene cause Beckwith-Wiedemann syndrome (BWS) and overgrowth, while missense mutations in the PCNA-binding motif are associated with IMAGe syndrome (Intrauterine Growth retardation, Metaphyseal Dysplasia, Adrenal Insufficiency, Genital abnormalities) PMID: 25258553
Created: 3 Apr 2017, 10:30 a.m.
From GeneReviews 2000 Mar 3, Shuman C et al [Updated 2016 Aug 11]. PMID:20301568
Single-gene testing. Sequence analysis followed by gene-targeted deletion/duplication analysis of CDKN1C should be considered in familial cases, in individuals with Beckwith-Wiedemann syndrome (BWS) and midline anomalies (cleft palate, posterior fossa abnormalities, omphalocele, or hypospadias (Gardiner et al 2012 PMID:22585446, Brioude et al 2015 PMID: 26077438), or in individuals for whom a strong clinical suspicion for BWS exists but no detectable chromosome 11p15.5 cytogenetic abnormalities, copy number variants, methylation abnormalities, or UPD has been identified.
Sequence analysis of CDKN1C can identify pathogenic variants in approximately 40% of familial cases and 5%-10% of cases with no family history of BWS (PMID:26077438, 9341892, 11414765, 10862080, 10424811, 9311733). Approximately 85% of individuals with BWS have no family history of BWS while approximately 15% have a family history consistent with autosomal dominant transmission of BWS.
Created: 31 Mar 2017, 9:47 a.m.

Publications

Sarah Leigh (Genomics England Curator)

Comment on list classification: This gene will remain red as pathogenicity is caused by changes to methylation of this gene
Created: 8 Jun 2016, 2:24 p.m.
Comment on list classification: This gene is being demoted to red as pathogenicity is caused by changes to methylation of this gene
Created: 8 Jun 2016, 2:23 p.m.

Ellen McDonagh (Genomics England Curator)

Promoted from red to green due to expert review. It is a confirmed DD gene for Beckwith-Wiedemann syndrome.
Created: 29 Mar 2016, 1:21 p.m.
"Clinical overlap between BWS and Sotos syndrome." Comment from Richard Scott (North Thames GMC/UCL), Oct. 9, 2015, 10:12 p.m.
Created: 29 Mar 2016, 1:21 p.m.
Mutational spectrum tested for by the UKGTN: loss of methylation at LIT1 (KvDMR1 within LIT1 - KCNQ1OT1 is the HGNC-approved symbol for LIT1), Hypermethylation of H19, duplication of paternally inherited 11p15 region, paternal uniparental disomy of 11p15 region, maternal H19 DMR microdeletion, maternal KvDMR1 microdeletion. ICR1 is the H19/IGF2-imprinting control region located in the 11p15.5 region.
Created: 29 Mar 2016, 1:20 p.m.

History Filter Activity

31 May 2019, Gel status: 3

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for gene: CDKN1C were changed from Beckwith-Wiedemann syndrome; OMIM 130650; IMAGE syndrome, 614732 to Beckwith-Wiedemann syndrome, 130650; IMAGE syndrome, 614732

31 May 2019, Gel status: 3

Set publications

Louise Daugherty (Genomics England Curator)

Publications for gene: CDKN1C were set to 20803657; 8841187; 20301568; 22585446; 26077438; 9341892; 26077438; 11414765; 10424811

31 May 2019, Gel status: 3

Set publications

Louise Daugherty (Genomics England Curator)

Publications for gene: CDKN1C were set to PMID: 20803657; 8841187; 20301568; 22585446; 26077438; 9341892; 26077438; 11414765; 10424811

25 May 2017, Gel status: 4

Set publications

Helen Brittain (Genomics England Curator)

Publications for CDKN1C were set to PMID: 20803657; 8841187; 20301568; 22585446; 26077438; 9341892; 26077438; 11414765; 10424811

25 May 2017, Gel status: 4

Gene classified by Genomics England curator

Helen Brittain (Genomics England Curator)

This gene has been classified as Green List (High Evidence).

8 Jun 2016, Gel status: 1

Gene classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

This gene has been classified as Red List (Low Evidence).

8 Jun 2016, Gel status: 1

Gene classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

This gene has been classified as Red List (Low Evidence).

29 Mar 2016, Gel status: 4

Gene classified by Genomics England curator

Ellen McDonagh (Genomics England Curator)

This gene has been classified as Green List (High Evidence).

29 Mar 2016, Gel status: 4

Set Phenotypes

Ellen McDonagh (Genomics England Curator)

Phenotypes for CDKN1C were set to Beckwith-Wiedemann syndrome; OMIM 130650; IMAGE syndrome, 614732

29 Mar 2016, Gel status: 4

Set mode of pathogenicity

Ellen McDonagh (Genomics England Curator)

Mode of pathogenicity for CDKN1C was changed to Other - please provide details in the comments

29 Mar 2016, Gel status: 0

Created

Ellen McDonagh (Genomics England Curator)

CDKN1C was created by ellenmcdonagh

29 Mar 2016, Gel status: 4

Added New Source

Ellen McDonagh (Genomics England Curator)

CDKN1C was added to Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorderspanel. Sources: Eligibility statement exclusion criteria,Expert Review Green,UKGTN,Radboud University Medical Center, Nijmegen