CDKN1C – Beckwith-Wiedemann syndrome

Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth disorder marked by macroglossia, hemihypertrophy, omphalocele, abdominal wall defects and a predisposition to embryonal tumours. CDKN1C (p57KIP2) is a maternally expressed cyclin-dependent kinase inhibitor on 11p15.5 that regulates G1/S transition and is silenced on the paternal allele by imprinting control region 2 (ICR2). Loss-of-function in the maternal CDKN1C allele disrupts this dosage balance and leads to the BWS phenotype.

Maternally inherited heterozygous CDKN1C variants follow an autosomal dominant pattern with paternal imprinting. Over 37 distinct coding mutations—including missense, frameshift and intronic splice‐site changes—have been documented in 50 unrelated probands with BWS (PMID:26077438) and segregate in at least seven multiplex families (PMID:10424811). This strong familial clustering and high penetrance of maternal transmission support a Definitive gene–disease association by ClinGen criteria.

The CDKN1C variant spectrum comprises missense substitutions within the cyclin-CDK inhibitory domain, frameshift/truncating mutations throughout exons 1–3, and deep‐intronic alterations affecting splicing enhancers. A representative missense change, c.150G>T (p.Trp50Cys), was identified in the first Indian pedigree with BWS, reinforcing the global mutational heterogeneity of CDKN1C (PMID:39502854).

Functional assays reveal that intronic G-tract mutations reduce splicing efficiency in cell lines and patient fibroblasts, implicating disrupted exon–intron recognition in disease pathogenesis (PMID:15150778). Missense and truncating mutants demonstrate loss of growth-suppressive activity in transfection assays, and some gain-of-function PCNA-binding‐domain variants show aberrant protein stabilization (PMID:24098681). Chromatin immunoprecipitation studies further indicate that repressive histone modifications at the CDKN1C promoter accompany gene silencing in BWS patients lacking ICR2 methylation defects (PMID:16061564).

Not all BWS cases harbour CDKN1C mutations; epimutations at ICR2 and paternal uniparental disomy of 11p15.5 can also downregulate CDKN1C expression without coding changes, highlighting genotype–epigenotype complexity. Nonetheless, CDKN1C mutation–positive patients show a higher prevalence of exomphalos and distinctive clinical features that guide targeted genetic testing and surveillance.

Integration of genetic and experimental data confirms a loss-of-function mechanism via haploinsufficiency and imprinting dysregulation. Clinical genetic testing for CDKN1C variants is essential for familial risk assessment, prenatal diagnosis and personalized tumour surveillance in BWS.

Key take-home: Maternal CDKN1C sequencing should be prioritized in BWS patients with abdominal wall defects or macroglossia and in familial cases, enabling definitive diagnosis and tailored clinical management.

References

• American journal of medical genetics. Part A • 2004 • CDKN1C mutation in Wiedemann-Beckwith syndrome patients reduces RNA splicing efficiency and identifies a splicing enhancer. PMID:15150778
• Journal of medical genetics • 1999 • Analysis of germline CDKN1C (p57KIP2) mutations in familial and sporadic Beckwith-Wiedemann syndrome (BWS) provides a novel genotype-phenotype correlation. PMID:10424811
• Human mutation • 2015 • Mutations of the Imprinted CDKN1C Gene as a Cause of the Overgrowth Beckwith-Wiedemann Syndrome: Clinical Spectrum and Functional Characterization. PMID:26077438
• PLoS one • 2013 • Increased protein stability of CDKN1C causes a gain-of-function phenotype in patients with IMAGe syndrome. PMID:24098681
• Journal of medical genetics • 2005 • Alternative mechanisms associated with silencing of CDKN1C in Beckwith-Wiedemann syndrome. PMID:16061564
• Journal of pediatric genetics • 2024 • CDKN1C -Related Beckwith-Wiedemann Syndrome: First Patient from India. PMID:39502854

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