CDKN1C – IMAGe syndrome

CDKN1C is a maternally expressed cyclin-dependent kinase inhibitor whose gain-of-function mutations underlie IMAGe syndrome, an autosomal dominant imprinting disorder characterized by intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita and genital anomalies. IMAGe syndrome was first linked to missense variants clustering in the PCNA-binding domain of CDKN1C in familial and unrelated cases, establishing a novel undergrowth phenotype distinct from Beckwith–Wiedemann syndrome (PMID:22634751). The maternal-only transmission and complete penetrance upon maternal inheritance underscore the critical role of imprinting at 11p15.5 in disease pathogenesis.

Genetic evidence includes at least 12 probands across seven unrelated families harboring CDKN1C missense changes (e.g., c.787G>A (p.Asp263Asn)) with autosomal dominant maternal segregation ([PMID:22634751]). Three siblings sharing a novel c.815T>G (p.Ile272Ser) variant demonstrated identical clinical features, confirming intra-family recurrence (PMID:24098681). Additional reports describe de novo and inherited p.Asp274Asn and p.Lys278Glu mutations in Japanese patients and a trio analysis, respectively, further expanding the allelic series and corroborating the maternal imprinting mechanism (PMID:24313804; PMID:25614875).

All pathogenic variants localize to a highly conserved hotspot within CDKN1C’s PCNA-binding domain (residues 263–279), with recurrent changes including p.Phe265Val, p.Arg268Pro, p.Asp274Asn and p.Phe276Val. No loss-of-function alleles have been associated with IMAGe, distinguishing the syndrome from BWS. Phenotypic heterogeneity is observed: some families manifest full adrenal insufficiency, while others display isolated growth restriction or Silver–Russell–like features without adrenal involvement, indicating variable expressivity and potential genetic heterogeneity.

Functional studies demonstrate that IMAGe-associated CDKN1C mutants lose PCNA binding but gain protein stability, resisting proteasomal degradation in cycloheximide chase assays, thereby augmenting CDKN1C’s cell-cycle inhibitory activity ([PMID:24098681]). Targeted expression of these variants in Drosophila induces severe eye-growth defects compared to wild-type CDKN1C, confirming a gain-of-function mechanism ([PMID:22634751]). These concordant experimental data support a model in which enhanced CDKN1C stability drives the undergrowth phenotype of IMAGe syndrome.

Segregation analyses consistently show maternal transmission of pathogenic alleles with full penetrance in affected offspring. No pathogenic variants have been found on the paternally inherited allele, and imprinting control disruptions at KvDMR1 have been ruled out in most cases. One report of an unaffected carrier mother highlights the necessity of maternal expression for disease manifestation, consistent with the imprinting model.

In summary, CDKN1C gain-of-function mutations in the PCNA-binding domain cause IMAGe syndrome through increased protein stability and enhanced cell-cycle inhibition. The association is supported by multiple unrelated families, clear segregation, and robust functional concordance. CDKN1C sequencing should be prioritized in patients with intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia, or genital anomalies, particularly when maternal transmission is evident. Key take-home: Pathogenic CDKN1C variants define a clinically actionable imprinting disorder with a gain-of-function mechanism, enabling precise genetic diagnosis and reproductive counseling.

References

• Nature genetics • 2012 • Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome. PMID:22634751
• PLoS one • 2013 • Increased protein stability of CDKN1C causes a gain-of-function phenotype in patients with IMAGe syndrome. PMID:24098681
• Clinical endocrinology • 2014 • IMAGe syndrome: clinical and genetic implications based on investigations in three Japanese patients. PMID:24313804
• Molecular genetics & genomic medicine • 2014 • Diagnosis of an imprinted-gene syndrome by a novel bioinformatics analysis of whole-genome sequences from a family trio. PMID:25614875

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